The NeuRX Diaphragm Pacing System. Image: Synapse Biomedical.

One of biggest challenges treating ALS is breathing difficulties which occur due to the gradual weakening and decline of the respiratory muscles.  Researchers nevertheless are working hard to develop treatment strategies to keep these respiratory muscles moving to help people with ALS breathe easier.

One potential strategy called phrenic pacing hopes to keep the diaphragm moving by boosting the stamina of the respiratory muscles through the implantation of a device that regularly stimulates the connecting nerves. The FDA-approved device, called the NeuRX diaphragm pacing system (DPS), is available by prescription for patients experiencing frequent trouble breathing (chronic hypoventilation).

But a group of physicians from Assistance Publique – Hôpitaux de Paris led by respiratory specialist Thomas Similowski MD PhD thinks that the NeuRX DPS could benefit a lot more people with ALS.  They suspect the device, introduced at the very first signs of breathing difficulties, might jump start the training of these muscles to keep the diaphragm moving even longer - postponing the need for non-invasive ventilation.

Now, the French team is gearing up to put their treatment strategy to the test in people with ALS.  The double-blind randomized clinical trial, called RespiStimALS, is to be conducted at the Pitié-Salpêtrière Hospital in Paris.  All participants are to be monitored three times monthly for 2 years.  Outcomes include: reductions in respiratory decline (forced vital capacity), improvements in sleep quality and overall survival.  74 people with ALS are expected to participate.

The trial is scheduled to begin in June 2012.

To learn more about the NeuRX DPS and how the device might help people with ALS, read DPS Sleep.  To read about the ongoing NeuRX DPS trial in the UK, check out UK Gears Up To Put DPS Through Its Paces.  To find out about other strategies to help people with ALS breathe easier, read CK-357, helping pALS live strong?

References

Gonzalez-Bermejo, J., et al. (2011) Diaphragm pacing improves sleep in patients with amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis. doi:10.3109/17482968.2011. 597862  Abstract | Full Text (Subscription Required)

Onders, R.P., et al. (2009) Complete worldwide operative experience in laparoscopic diaphragm pacing: results and differences in spinal cord injured patients and amyotrophic lateral sclerosis patients. Surgical Endoscopy, 23(7): 1433-1440.  Abstract | Full Text (Subscription Required)

Further Reading

Ducko, C. (2011) Clinical advances in diaphragm pacing. Innovations: Technologies and Techniques in Cardiothotacic and Vascular Surgery 6(5), 289-297. Abstract | Full Text (Subscription Required)

Marion, D.W. (2011) Diaphragm Pacing.  UpToDate.  Excerpt |  Full Text (Subscription Required)  

Patient Resources

Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation (RespiStimALS). Contact | ALS TDI | Website 

Diaphragm Pacing in Motor Neuron Disease (DiPALS) Study. Contact | ALS TDI | Website 

 

Keep out.  The blood brain and spinal cord barriers fortify the walls of tiny blood vessels that snake through the brain and spinal cord - preventing toxic substances in the blood from entering the central nervous system. Image: Ben Brahim Mohammed, Wikimedia Commons.

More than 100 medicines have been tested as possible treatments for ALS. But only riluzole is FDA-approved: a drug that at best, moderately treats the disease.

A considerable obstacle toward developing more effective treatments for neurologic diseases including ALS is the blood brain and spinal cord barriers which in part, keep certain toxic substances circulating in the blood out of the central nervous system. These cellular-based barriers block potential medicines from getting into the brain and spinal cord. And, drug pumps called ABC transporters installed within these barriers kick drugs that sneak into ALS-ravaged nerves back out into the blood.

But according to a new study led by Thomas Jefferson University neuroscientist Davide Trotti PhD in Pennsylvania, creating medicines for ALS might be especially challenging because two of these drug pumps appear to kick into high gear over the course of the disease.  

The researchers found that levels of ABC transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) increased in people with ALS.  And in mice, these pumps appeared to kick out over 50% more drugs from the spinal cord.

These ABC transporters are the same drug pumps demonstrated previously by scientists at Université Paris-Sud in France to have the ability to kick riluzole out of the brain.

The results are published this month in Neurobiology of Disease.

The US team measured the levels and pumping action of 8 ABC transporters in the blood brain and spinal cord barriers in two mouse models of ALS.

 

Going out?  Drug pumps (purple) embedded in the blood brain and spinal cord barriers may kick potential ALS medicines (blue) out of the central nervous system (CNS) over the course of the disease - rendering them much less effective.  Adapted from Osherovich, L. (2009), SciBX. Courtesy of Nature Publishing Group. All rights reserved.

The team found that the numbers of two of these drug pumps – P-glycoprotein and breast cancer resistance protein (BCRP) - appeared to increase at clinical onset - up to nearly doubling over the course of the disease. 

The drug pump boost appeared to be localized to the motor cortex (muscle-moving region of the brain) and the spinal cord.  The same regions ravaged by the disease.

The results demonstrate the importance of rigorous preclinical testing of emerging ALS drugs before making go/no-go decisions. This includes chronic dosing studies to determine the appropriate dosing strategy to use during testing to ensure adequate delivery to the brain and spinal cord throughout the course of the disease.    

Looking ahead, the team suggests testing combination therapies that include pump blockers such GlaxoSmithKline’s elacridar and Xenova’s tariquidar to boost CNS exposure and maximize drug efficacy.  First introduced as a potential therapeutic option for drug-resistant cancers, such strategies are also being tested as a possible treatment for antibiotic-resistant bacterial infections.

References

Jablonski, M.R., Jacob, D.A., Campos, C., Miller, D.S., Maragakis, N.J., Pasinelli, P. and Trotti D. (2012) Selective increase of two ABC drug efflux transporters at the blood-spinal cord barrier suggests induced pharmacoresistance in ALS. Neurobiology of Disease doi:10.1016/j.nbd.2012.03.040. Abstract | Full Text (Subscription Required)

Milane, A., Fernandez, C., Dupuis, L., Buyse,M., Loeffler, J.-Philippe, Farinotti, R.,Meininger, V. and Bensimon, G., 2010. P-glycoprotein expression and function are increased in an animal model of amyotrophic lateral sclerosis. Neuroscience Letters 472(3), 166–170. Abstract | Full Text (Subscription Required)

Milane, A., Vautier, S., Chacun, H., Meininger, V., Bensimon, G., Farinotti, R. and Fernandez, C. (2009) Interactions between riluzole and ABCG2/BCRP transporter. Neuroscience Letters 452(1), 12–16. Abstract | Full Text (Subscription Required)

Boston-Howes, W., Williams, E.O., Bogush, A., Scolere, M., Pasinelli, P. and Trotti, D. (2008) Nordihydroguaiaretic acid increases glutamate uptake in vitro and in vivo: therapeutic implications for amyotrophic lateral sclerosis. Experimental Neurology 213(1), 229–237. Abstract | Full Text

Milane, A., Fernandez, C., Vautier, S., Bensimon, G., Meininger, V. and Farinotti, R. (2007) Minocycline and riluzole brain disposition: interactions with p-glycoprotein at the blood–brain barrier. Journal of Neurochemistry 103(1), 164–173. Abstract | Full Text (Subscription Required)

Further Reading

Neuwelt, E.A. et al. (2011) Engaging neuroscience to advance translational research in brain barrier biology. Nature Reviews Neuroscience 12(3), 169-182. Abstract | Full Text (Subscription Required) 

Löscher, W. and Potschka, H. (2005) Drug resistance in brain diseases and the role of drug efflux transporter. Nature Reviews Neuroscience 6(8), 591-602. Abstract | Full Text (Subscription Required) 

 

Transplant stat.  Emory University School of Medicine neurosurgeon Nicholas Boulis MD injected between 0.5 and 1 million neural stem cells (above) in the lumbar section of ALS patients' spinal cords. Image: Corey Seehus, Brain Cells Inc for the 2010 GE Healthcare Image Competition.

Researchers estimate that more than 70% of motor neurons could be lost in people with ALS just one year after being diagnosed with the disease. To stem the tide of neurodegeneration, scientists are working hard to develop neuroprotective therapies to help keep their muscles moving.

One such potential treatment strategy, being developed by Maryland’s Neuralstem Inc., hopes to deploy neuronal bodyguards into the spinal cord that crank out protective substances which may shield the motor nerves from further destruction. The experimental stem cell transplantation procedure, performed during surgery, involves the direct injection of healthy neural stem cells into the spinal cord. The transplanted stem cells according to preclinical studies may give rise to populations of so-called interneurons that might plug directly into ALS-ravaged motor neurons, providing them life support.

In 2010, US physicians launched a phase I clinical trial to evaluate the safety of Neuralstem’s stem cell transplantation procedure. Patients received stem cell injections in the lumbar (leg-moving) region of the spinal cord. 12 people with ALS participated. 

Now, the team reports the first results from the phase I clinical trial.

The stem cell transplantation procedure appears to be safe and does not appear to aggravate the disease.  But, the immunosuppressants prescribed to prevent rejection of these transplanted stem cells were not well-tolerated by trial participants.

The results are published in the journal Stem Cells.

Emory University School of Medicine neurosurgeon Nicholas Boulis MD injected up to 1 million neural stem cells into the spinal cords of 12 ALS patients post-laminectomy.  Patients received anti-rejection medicines routinely used in whole organ transplants before and after surgery.

The team found that the procedure appeared to be safe and 6 to 18 months later did not rapidly worsen patients’ condition according to ALS-FRS, forced vital capacity and other functional measures. 

But researchers discovered that ALS patients could not tolerate the immunosuppressants (mycophenolate mofetil and tacrolimus) prescribed post-surgery.  Most trial participants had to drop or reduce the dosage of at least one of the two anti-rejection medicines due to chronic bloating, diarrhea and vomiting.  And, 2 out of 12 patients had to be taken off both drugs altogether due to the inability to control these symptoms through other medications.

 

Under adult supervision. Scientists are creating potentially neuroprotective astrocyte-like cells from adult (mesenchymal) stem cells obtained from the patient's own bone marrow in hopes to slow down the disease. Image: Stem Cell Institute, Panama.

The jury is still out however whether a personalized stem cell therapy such as Brainstorm Cell Therapeutics’ NurOwn is a better way to go – particularly for people with inherited forms of ALS. The treatment strategy, which uses the patients’ own bone marrow to generate neurotrophin-producing cells, eliminates the need for immunosuppressants. But these transplanted cells according to some experts contain potentially ALS-triggering mutations which might also further contribute to the disease.

Neuralstem’s phase I clinical trial remains ongoing. Six people with ALS are expected to be implanted with stem cells in the cervical (diaphragm-moving) region of the spinal cord sometime this spring or summer. The trial is expected to be completed in October 2012.

Brainstorm Cell Therapeutics’ NurOwn phase I/II clinical trial is currently ongoing in Israel. Researchers are expected to launch a phase I/II ALS clinical trial in the US sometime in 2012.

References

Glass, J.D., Boulis, N.M., Johe, K., Rutkove, S.B., Federici, T., Polak, R., Kelly, C. and Feldman, E.L.(2012) Lumbar intraspinal injection of neural stem cells in patients with ALS: results of a phase I trial in 12 patients. Stem Cells, doi:10.1022/ stem.1079. Abstract | Full Text (Subscription Required)

Xu, L., Ryugo, D.K., Pongastaporn, T., Johe, K. and Koliatsos, V.E. (2009) Human neural stem grafts in the spinal cord of SOD1 transgenic rats: differentiation and structural integration into the segmental motor circuitry. Journal of Comparative Neurology 514(4), 297-309. Abstract | Full Text

Xu, L., Yan, J., Chen, D. Welsh, A.M., Hazel, T., Johe, K., Hatfield, G. and Koliatsos, V.E. (2006) Human neural stem cell grafts amerliorate motor neuron disease in SOD-1 transgenic rats. Transplantation 82(7), 865-875. Abstract | Full Text (Subscription Required)

Further reading

Boulis, N.M., Federici, T., Glass, J.D., Lunn, J.S., Sakowski, S.A. and Feldman, E.L. (2012) Translational stem cell therapy for amyotrophic lateral sclerosis. Nature Reviews Neurology 8(3), 172-176. Abstract | Full Text (Subscription Required) 

Maragakis N.J. (2010). Stem cells for the neurologist. Amyotrophic Lateral Sclerosis, 11(5), 417-423.  Abstract| Full Text (Subscription Required)

Patient Resources

Human Spinal Cord Derived Neural Stem Cell Transplantation for the Treatment of Amyotrophic Lateral Sclerosis (ALS)  ALSTDI | Website | Contact

Autologous Cultured Mesenchymal Bone Marrow Stromal Cells Secreting Neurotrophic Factors (MSC-NTF), in ALS Patients. ALSTDI | Website | Contact 

Note: We will update this information when details in regards to Brainstorm's US trial become available.

 

Lights camera action potential.  Scientists recreated diseased motor neurons by reprogramming skin cells from a person with a rare inherited form of ALS linked to a mutation in TDP-43. Adapted from Bilican, B et al. (2012). Courtesy of the National Academy of Sciences Press.  All rights reserved.

For more than 150 years, ALS has been recognized by experts as a motor neuron disease. But scientists still remain unsure why these cells are especially vulnerable to destruction in people with ALS or why they ultimately fail during the course of the disease.

An international group of neuroscientists led by University of Edinburgh’s Siddharthan Chandran MD PhD, King’s College London’s Christopher Shaw MBChB MD FRACP FRCP and Columbia University’s Tom Maniatis PhD hopes to begin to answer these questions by recreating ALS-ravaged motor neurons in laboratory dishes and studying their neurodegeneration.

Now, the UK-US research team reports that they have hit their first milestone: the generation of a so-called induced pluripotent stem (iPS) cell line created from an ALS patient skin biopsy that can be used to cook up motor neurons in the laboratory. Incredibly, the motor neurons induced appear to be in working order - capable of firing electrical signals used to 'tell' muscles to move - and exhibit tell-tale signs of the disease.

This is the first time that researchers have been able to recreate apparently functional motor neurons in the laboratory from a person with ALS.

The study is published this month in the Proceedings of the National Academy of Sciences.

 

Not an exact match. Researchers discovered that induced ALS motor neurons accumulate misfolded TDP-43 (green). But unlike more than 90% of people with ALS, these aggregates do not build up in the cytoplasm. Image: Bilican, B et al. (2012).  Courtesy of the National Academy of Sciences Press.  All rights reserved.

The UK-US research team created a 'line' of ALS iPS cells by turning back the cellular clocks of a patient's skin cells and culturing them. The scientists then splashed these iPS cells with a few chemicals to push them into motor neuronal mode.

Peering under the microscope, the researchers found that the resulting motor neurons somewhat resembled those in people with ALS. The cells were nearly 3-times more prone to degeneration. And, misfolded proteins accumulated in them.

Meanwhile, neuroscientists at Nationwide Children’s Hospital in Ohio hope to up the ante by introducing key inflammation instigators such as microglia and astrocytes into the mix to truly recreate ALS in laboratory dishes. Just last September, the research team led by neuroscientist Brian Kaspar PhD reported the successful reconstitution, using spinal cord tissue from ALS patients, of a key aspect of astrocytosis – the astrocyte-mediated destruction of neighboring motor neurons - which in part fuels the progression of the disease.

Looking ahead, these cellular systems could help scientists uncover underlying mechanisms of ALS and at the same time, pave the way toward the development of personalized therapies to treat the disease.

To find out more about how scientists hope to use stem cells to better understand why motor neurons degenerate in people with ALS, read Dishing ALS. 

References

Bilican, B. et al. (2012) Mutant induced pluripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proceedings of the National Academy of Sciences, doi:10.1073/ pnas.1202922109. Abstract | Full Text (Open Access)

Haidet-Phillips, A.M. et al. (2011) Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nature Biotechnology, 29(9), 824-8. Abstract | Full Text (Subscription Required)

Further Reading

Son, E.Y., Ichida, J.K., Wainger, B.J., Toma, J.S., Rafuse, V.F., Woolf, C.J. and Eggan, K. (2011). Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell, 9(3), 205-218. Abstract | Full Text (Open Access)

Dimos, J.T. et al. (2008) Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218-1221. Abstract | Full Text (Subscription Required)

Di Giorgio, F.P., Boulting, G.L., Bobrowicz, S., and Eggan, K.C. (2008). Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. Cell Stem Cell, 3(6), 637-648. Abstract | Full Text (Subscription Required)

Marchetto, M.C., Muotri, A.R., Mu, Y., Smith, A.M., Cezar, G.G., and Gage F.H. (2008). Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell, 3(6), 649-657. Abstract | Full Text (Subscription Required)

 

Bundle of nerves. Scientists at BrainStorm Cell Therapeutics hope to use patient-derived astrocyte-like cells to boost supplies of the neurotrophin GDNF in people with ALS. Image: Protein Data Bank. 

In people with ALS, the motor nerves deteriorate leading to muscle weakness and ultimately paralysis.  In hopes to stop this neurodegeneration in its tracks, researchers are looking towards substances called neutrophins including BDNF, GDNF, IGF-1 and VEGF  to keep nerves healthy and plugged into muscles.  But delivering these protective substances safely at the right place, at the right time and at the right dose has turned out to be extremely difficult to do.  And, scientists remain unsure which one of these neurotrophins is the best choice for people with ALS to protect the motor nerves from further deterioration.

Studies suggest that moderate aerobic exercise such as stationary bicycling or treadmilling might have the potential to help keep muscles and nerves healthy longer in people with ALS by increasing levels of many of these protective substances in the brain and spinal cord. What’s more, a moderate workout might even help fight the disease by boosting energy supplies, removing damaged proteins and reducing inflammation.

Neurologists nevertheless remain reluctant to recommend specific exercise routines for their patients.  There simply is not enough clinical evidence according to experts to indicate which routines are safe and offer the most benefit to people with ALS.  New clinical trials promise to change that by putting exercise to the test in people with ALS.

Run, mouse, run

Exercise can keep your heart healthy and keep your spirits up. But according to experts, a short workout might do a lot more good for people with ALS. Certain forms of moderate aerobic exercise might help keep nerves plugged into muscles and protect them from destruction.

 

Mighty mouse.  Researchers often study the underlying benefits of moderate aerobic exercise in mice by providing a running wheel.  Image: Salk Institute of Biological Studies, San Diego.

Researchers first suspected that exercise might benefit people with ALS upon the discovery in the mid 1990s that a short aerobic workout boosted levels of neurotrophins - substances that protect motor neurons or trigger the growth of new motor neurons - in the brain. A team led by University of California Irvine neuroscientist Carl Cotman PhD reported in 1995 in rats that running for one week increased levels of BDNF in the brain more than two-fold.  And, researchers from the Cajal Institute in Madrid reported in 2000 and 2001 that increased levels of the neurotrophin IGF-1 following moderate aerobic exercise helped to protect the brain in rats from injury or neurodegenerative disease.

Scientists subsequently discovered that moderate aerobic exercise increased circulating levels of a number of neurotrophins in people including those with multiple sclerosis or a spinal cord injury.

Encouraged by the ability of short aerobic workouts to boost neuroprotective mechanisms, researchers in the early 2000s tested ALS mice to determine whether or not such routines could help slow down the disease.  In 2003 and 2005, scientists reported that running moderately increased the lifespan of ALS mice.  And, in 2009, scientists from the Université de Paris Descartes found that swimming significantly delayed clinical onset and dropped losses of motor neurons in the spinal cord of ALS mice by nearly 50%.

The power of exercise

 

Growth spurt. Scientists discovered that moderate exercise induces the production of protective factors in the CNS. Here, the levels of BDNF are shown (yellow, red) in the brain of an exercised (b) vs. non-exercised (a) mouse. Adapted from Neeper, S.A. et al. (1995), Nature. Courtesy of Nature Publishing Group. All rights reserved.

Researchers however suspect that moderate aerobic exercise might have the potential to do much more to keep the motor nerves healthy in people with ALS. Exercise may help keep the power on in the motor nerves by boosting levels of oligodendrocytes: critical cells in the brain and spinal cord that are thought in part, to supply critical energy-making ingredients to mitochondria keeping the energy flowing in distal axons and nerve terminals.   Reporting in 2011, scientists from the University of California in Los Angeles found that mice that frequented the running wheel for one week boosted numbers of oligodendrocyte precursors called NG2+ cells more than two-fold in the spinal cord.  And, in 2009, scientists from the Université de Paris Descartes found that ALS mice which swam regularly maintained near healthy levels of spinal cord oligodendrocytes compared to unexercised mice which lost nearly a third of their oligodendrocytic populations.

What's more, exercise might keep neuroinflammation in check.  Researchers at the Université de Paris Descartes reported in 2009 that swimming regularly dropped levels of activated astrocytes in ALS mice to nearly those of healthy mice – reducing levels of potentially damaging inflammatory cytokines in the spinal cord.  And, scientists at the University of Illinois in Urbana reported in 2011 that providing access to a running wheel increased levels of microglia producing IGF-1 more than two-fold in healthy mice suggesting that moderate aerobic exercise might help push microglia from the neurotoxic to the neuroprotective mode.

“The potential effects of exercise are diverse,” says Johns Hopkins University School of Medicine Neurologist Nicholas Maragakis MD.  “That’s what makes exercise so appealing.”

And, these potential benefits might just be the tip of the iceberg.  A moderate aerobic workout according to a recent study in mice might even switch on intracellular vacuum cleaners within the motor nerves, reducing inflammation.  Called autophagosomes, these mini Hoovers could help keep levels of neuronal destruction down by swallowing up aggregated proteins and malfunctioning mitochondria that accumulate during the course of the disease - dropping levels of reactive oxygen species (ROS) that further deteriorate the motor nerves.  Looking ahead, the Baylor College of Medicine team hopes to evaluate whether or not this so-called exercise-induced autophagy could help protect against neurodegenerative disease.

"We do know that autophagy is likely a protective mechanism against these diseases," says Baylor College of Medicine internist Beth Levine MD who led the study. "Increasing autophagy may be a strategy to treat them."

Of mice to men

Translating these moderate aerobic workouts into specific routines for people with ALS however has been extremely challenging to do. And, the implementation of physical exercise into routine practice remains hotly debated and extremely controversial.

 

Spinning wheels. A growing number of researchers suspect that moderate aerobic exercise such as stationary bicycling might be helpful to people with ALS. But the use, the intensity and the duration of such routines remain controversial. Image: sirwiseowl, Flickr. 

Some neurologists worry that regular exercise could speed up the progression of the disease by turning up the production of reactive oxygen species (ROS), potentially damaging weakening muscles and increasing inflammation of the connecting nerves.

But a growing number of neurologists argue that physical inactivity could expose people with ALS to even greater health risks.  And, exercise in moderation could bring the benefits of exercise while minimizing the risk of worsening their condition.

“I do think that mobility is important,” says Johns Hopkins neurologist Nicholas Maragakis MD. “I usually tell them to exercise on an every other day basis.  [But] I don’t want them to be fatigued or have any muscle pain following an exercise regimen.” 

Most clinical studies on the books that evaluate the benefits and risks of exercise comes from studies that involve people with other neuromuscular diseases – particularly complications due to polio - not ALS.   

“There is no evidence that exercise is harmful to people with ALS,” says Oxford University neurologist Martin Turner MA PhD MRCP.  

Many neurologists therefore find themselves in a Catch-22.  Exercise could be helpful and could be good for the overall wellness of their patients.  But how much exercise is enough but not too much?  What kinds of workouts should they do?

With existing randomized controlled exercise studies extremely limited and conducted in fewer than 25 people with ALS, neurologists are unable to figure out which kinds of exercise are safe and offer the most benefits at the lowest risk for their patients.

“We need to know which type of exercise at what duration and intensity could be protective,” explains INSERM – Strasbourg neuroscientist Luc Dupuis PhD.

We can work it out

University of Lisbon physician Anabela Pinto MD PhD grew frustrated in the mid 1990s that she could not do more for her patients with ALS.  Noninvasive ventilation appeared to extend survival but did not improve their quality of life or slow down their disease.  In hopes to change that, she began to introduce exercise into their daily routine.

 

Sweet oxygen. Experts perform cardio pulmonary exercise testing (CPET) to determine the maximum output of oxygen (VO2 max): a critical benchmark that indicates to researchers the point at which muscles could be overworked or damaged. Image: Salem Elizabeth, Flickr. 

Reporting in 1999, the University of Lisbon physicians found that a group of 8 people with ALS who exercised showed significant reductions in decline of breathing abilities after one year of rehabilitation (FVC, P < 0.002).  20 people with ALS participated in the controlled clinical trial.

The strategy her Santa Maria Hospital -based team developed is loosely based on a typical cardiac stress test.  Exercise either on a cycle ergometer or a treadmill ramped up to 60-65% oxygen output (about 70-75% heart rate) for about 10-20 minutes - sufficient intensity to keep weakening muscles moving but not overworking or damaging them.  Workouts are typically scheduled three times per week.

The idea: By performing aerobic exercise regularly for a short period of time, the team hopes to keep fast-twitch muscles critical to maintain optimal breathing rate and to power rapid motions moving; muscles which are especially vulnerable to atrophy in people with ALS.  

In subsequent years, the team implemented this supervised exercise program in their Lisbon-based clinic.  Non-invasive ventilation and body-weight support systems are provided if needed.

“Our current practice is to include exercise throughout the clinical evolution of the disease,” says Pinto.

Reporting the first results of her latest exercise study at the 2011 ALS/MND meeting in Australia last December, the University of Lisbon team found that people with ALS on this supervised exercise regimen showed significant signs of reduced functional decline (ALS-FRS) and increased survival post-rehabilitation (p = 0.04) over a one year period.  40 patients participated.

Now, the Santa Maria Hospital-based team is working hard to adapt these exercises for home use. And at the same time, the team is adjusting these routines to accommodate people with ALS that might have trouble adhering to such regular workouts due to deficits in executive function, estimated to affect as many as 50% of people with the disease.

“I am really interested in making this [exercise] program available to as many patients as possible,” says Pinto.

But the Neuromuscular Unit at Santa Maria Hospital is small.  The team’s aerobic exercise routines have only been tested in a few people with ALS.  Larger studies are needed according to experts to implement specific therapeutic workouts into routine practice.

 

NMJ Unplugged. In people with ALS, neuromuscular junctions can become unstable leading to the nerves being unplugged from muscles ultimately resulting in paralysis. Exercise may help stabilize these connections according to experts. John Wildgoose, Wellcome Images.

Now, a group of neurologists led by Johns Hopkins University School of Medicine neurologist Nicholas Maragakis MD are stepping up to the plate by launching a clinical trial to evaluate the benefits of exercise in people with ALS.  The clinical trial, which will take place over six months in four centers in the US, will put three forms of moderate exercise to the test in people with ALS: stationary bicycling (aerobic exercise), weightlifting (resistance exercise) and stretching (the standard of care).  Patients will be monitored for improvements in muscle strength/fatigue, signs of reduced functional decline and quality of life.  About 60 people with possible, probable or definite ALS are expected to participate. 

“The trial's power is to really study the safety and tolerability of exercise [in people with ALS],” explains Johns Hopkins School of Medicine neurologist Nicholas Maragakis MD.  “I think that will go a long way.”

Researchers however anticipate that workouts that experts ultimately develop for people with ALS will extend well outside the exercise gym.  By understanding the underlying mechanisms behind the benefits of these workouts, scientists hope to gain insight into the underlying mechanisms of this exercise-based neuroprotection to help them develop more effective medicines to fight the disease.

Scientists at Johns Hopkins School of Medicine hope to identify the underlying benefit of any workout found to be helpful in a future clinical trial by measuring levels of circulating neurotrophins and possibly looking for changes in muscle fiber composition in people with ALS following exercise.

The findings according to Luc Dupuis PhD, also at Germany's University of Ulm, could help scientists figure out how to fight one of the hardest aspects of the disease: denervation, when the motor nerves become unplugged from muscles leading to weakness and paralysis.

“During exercise, neuromuscular junctions are strengthened and stabilized,” explains Dupuis.  “Understanding what really happens during exercise might lead to a therapeutic strategy to treat ALS.” 

References - Clinical Studies

Lui, A.J. and Byl, N.N. (2009) A systematic review of the effect of moderate intensity exercise on function and disease progression in amyotrophic lateral sclerosis. Journal of Neurological Physical Therapy 33, 68-87. Abstract | Full Text  (Subscription Required)

Dalbello-Haas V, Florence JM, Krivickas LS. (2008) Therapeutic exercise for people with amyotrophic lateral sclerosis or motor neuron disease. Cochrane Database of Systematic Reviews 2, CD005229. Abstract | Full Text  (Subscription Required)

Rojas Vega, S., Abel, T., Lindschulten, R., Hollmann, W., Bloch, W. and Strüder, H.K. (2008) Impact of exercise on neuroplasticity-related proteins in spinal cord injured humans. Neuroscience 153(4), 1064-1070. Abstract | Full Text (Subscription Required)

Bello-Haas, V.D., Florence, J.M., Kloos, A.D., Scheirbecker, J., Lopate, G., Hayes, S.M., Pioro, E.P. and Mitsumoto, H. (2007) A randomized controlled trial of resistance exercise in individuals with ALS. Neurology 68, 2003-2007. Abstract | Full Text (Subscription Required)

Gold, S.M., Schulz, K.H., Hartmann, S., Mladek, M., Lang, U.E., Hellweg, R., Reer, R., Braumann, K.M. and Heesen C. (2003)  Basal serum levels and reactivity of nerve growth factor and brain-derived neurotrophic factor to standardized acute exercise in multiple sclerosis and controls. Journal of Neuroimmunology 138(1-2), 99-105. Abstract | Full Text (Subscription Required)

Drory VE, Goltsman E, Reznik JG, Mosek A, Korczyn AD. (2001) The value of muscle exercise in patients with amyotrophic lateral sclerosis.  Journal of Neurological Sciences 191, 133-137. Abstract | Full Text (Subscription Required)

Pinto, A.C., Alves, M., Nogueira, A., Evangelista, T., Carvalho, J., Coelho, A., de Carvalho, M. and Sales-Luís, M.L. (1999) Can amyotrophic lateral sclerosis patients with respiratory insufficiency exercise? Journal of Neurological Sciences 169, 69-75. Abstract | Full Text (Subscription Required)

References - Preclinical Studies

He, C. et al. (2012) Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481, 511-5. Abstract | Full Text (Subscription Required)

Kohman, R.A., Deyoung, E.K., Bhattacharya, T.K., Peterson, L.N. and Rhodes, J.S. (2011) Wheel running attenuates microglia proliferation and increases expression of a proneurogenic phenotype in the hippocampus of aged mice. Brain, Behavior and Immunity doi 10.1016/j.bbi.2011.10.006. Abstract | Full Text (Subscription Required)

Krityakiarana, W. et al. (2010) Voluntary exercise increases oligodendrogenesis in the spinal cord. International Journal of Neuroscience 120(4), 280-290. Abstract | Full Text  

Nave, K.A. (2010) Myelination and the trophic support of long axons. Nature Reviews Neuroscience 11(4), 275-283. Abstract | Full Text (Subscription Required)

Deforges, S., Branchu, J., Biondi,O., Grondard, C., Pariset, C., Lécolle, S., Lopes, P., Vidal, P.P., Chanoine, C. and Charbonnier, F. (2009) Motor neuron survival is promoted by specific exercise in a mouse model of amyotrophic lateral sclerosis. Journal of  Physiology 587, 561-572. Abstract | Full Text

Kaspar, B.K., Frost, L.M., Christian, L., Umapathi, P. and Gage, F.H. (2005) Synergy of insulin-like growth factor-1 and exercise in amyotrophic lateral sclerosis. Annals of Neurology 57(5), 649-655. Abstract | Full Text (Subscription Required)

Kirkinezos, I.G., Hernandez, D., Bradley, W.G. and Moraes, C.T. (2003) Regular exercise is beneficial to a mouse model of amyotrophic lateral sclerosis. Annals of Neurology 53(6), 804-807. Abstract | Full Text (Subscription Required)

Carro, E., Trejo, J.L., Busiguina, S. and Torres-Aleman, I. (2001) Circulating insulin-like growth factor I mediates the protective effects of physical exercise against brain insults of different etiology and anatomy. Journal of Neuroscience 21(15), 5678-5684.  Abstract | Full Text (Subscription Required)

Carro, E., Nunez, A., Busiquina, S. and Torres-Aleman I.   (2000) Circulating Insulin-like growth factor 1 mediates effects of exercise on the brain. Journal of Neuroscience 20, 2926-2933. Abstract | Full Text (Subscription Required)

Itoh, H., Ohkuwa, T., Yamamoto, T., Sato, Y., Miyamura, M. and Naoi, M. (1998) Effects of endurance physical training on hydroxyl radical generation in rat tissues. Life Sciences 63(21), 1921-1929. Abstract | Full Text (Subscription Required)

Neeper, S.A., Góauctemez-Pinilla, F., Choi, J. and Cotman, C. (1995) Exercise and neurotrophins. Nature 373, 109. Abstract | Full Text (Subscription Required)

Further reading

Lopes de Almeida, J. P., Silvestre, R., Pinto A. C., and de Carvalho, M. (2012) Exercise and amyotrophic lateral sclerosis.  Neurological Sciences 33, 9-15. Abstract | Full Text (Subscription Required)

Ashworth, N.L., Satkunam, L.E. and Deforge, D. (2012) Treatment for spasticity in amyotrophic lateral sclerosis/motor neuron disease.  Cochrane Database of Systematic Reviews 2, CD004156.  Abstract | Full Text  (Subscription Required)

Patient Resources

Trial of Resistance and Endurance Exercise in Amyotrophic Lateral Sclerosis (ALS)  ALSTDI | Website | Contact

 

Power gain.  CK-357 may boost the power of fast skeletal muscles by increasing their sensitivity to weak electrical impulses generated by deteriorating motor nerves. CK-357 might be particularly useful to boost diaphragm function because these muscles contain nearly 50% fast-twitch muscle fibers. Courtesy of Nature Publishing Group. All Rights Reserved.

In people with ALS, the diaphragm and intercostal muscles gradually weaken often leading to respiratory distress and failure.  In hopes to keep these muscles moving, Case Western University School of Medicine surgeon Raymond Onders MD FACS introduced a device, now approved by the FDA for people with ALS with breathing difficulties, called the NeuRX DPS which may boost the stamina of these muscles.  

But researchers from San Francisco’s Cytokinetics Inc. think that they might have a simpler solution: the experimental drug CK-2017357 (CK-357). Introduced in 2008, CK-357 might increase the strength of certain skeletal muscles including those needed for breathing. Now, Cytokinetics scientists reveal just how CK-357 works: the drug promises to make the most of weakening neuromuscular junctions by helping fast twitch fibers in skeletal muscles hold on to calcium, enabling more powerful contractions.  This so-called fast skeletal muscle is needed in part, to maintain a healthy breathing rate.

The Cytokinetics’ team anticipates that the drug could be beneficial in the treatment of number of neuromuscular diseases including ALS.

 

Sensitive muscle? Electrical signals from the motor nerves enable skeletal muscles to move by pulling the wrench out of the muscular works - troponin - through the release of calcium. CK-357 may strengthen muscles by increasing the affinity of fast skeletal troponin for calcium, boosting the power of these contractions. Adapted from Nature Education. Original source: Lehman, W. et al. (1994). Courtesy of Nature Publishing Group. All Rights Reserved.

Performance testing

Physicians are currently evaluating the safety and tolerability of multiple doses of CK-357 in people with ALS.  The multi-institutional US team, led by State University of New York neurologist Jeremy Shefner MD PhD, are also checking for improvements in patients’ muscle function including breathing ability.  The two 14 day placebo-controlled phase II clinical trials are expected to be completed by the end of March 2012. About 48 ALS patients are participating.

Meanwhile, researchers in England and France are gearing up to put the NeuRX DPS to the test to determine whether the device improves the quality of life and extends survival of people with ALS. The first results of these clinical trials are expected in early 2015.

Reference

Russell, A.J. et al. (2012) Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases. Nature Medicine doi:10.1038/nm.2618. Abstract | Full Text (Subscription Required)

Further Reading

Hardiman, O., van den Berg, L.H. and Kiernan, M.C. (2011) Clinical diagnosis and management of amyotrophic lateral sclerosis. Nature Reviews Neurology 7(11), 639-649. Abstract | Full Text (Subscription Required)

Hardiman, O. (2011) Management of respiratory symptoms in ALS. Journal of Neurology 258(3), 359-365. Abstract | Full Text (Subscription Required)

Patient Resources

Please note: These clinical trials are ongoing but are not recruiting.

A Study to Evaluate the Effects of Multiple Doses of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis (ALS)  ALSTDI | Website | Contact

Dose Titration Study to Test Safety and Effects of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis (ALS)  ALSTDI | Website | Contact 

 

FTLD Explained.  FTLD occurs when certain regions of the brain including those involved in executive function - critical thinking, problem solving and complex decision-making - shrink (red) due to neuronal loss.  FTLD is also known as frontotemporal dementia (FTD).  Here, an MRI of a person with a form of FTLD similar to ALS-FTLD is shown. Adapted from Whitwell, J.L. and Josephs, K.A. (2012). Courtesy of Nature Publishing Group. All Rights Reserved.

Neurologists may need to keep an eye out for cognitive and behavioral changes in people showing signs of ALS, according to a new study. 

The research team, led by Trinity College Dublin neurologist Orla Hardiman MD FRCP, found that 50% of people examined with the most common form of familial ALS identified to date also showed signs of frontotemporal lobar degeneration (FTLD).  The brain disorder might result in difficulties in critical thinking, problem solving and making complex decisions.

The study, which included 20 people with familial ALS harboring repeat expansions in the C9ORF72 gene, is the first to clinically describe this form of ALS.

The results are published in the March issue of Lancet Neurology.

Scientists first suspected that ALS might fall on the same clinical spectrum as FTLD in 2000 when a research team led by Massachusetts General Hospital neurologist Robert Brown MD PhD identified families with a history of both diseases. Just last fall, two independent research teams discovered one such cause of this so-called ALS with FTLD: repeat expansions in the gene, C9ORF72. 

Now, researchers report that people harboring repeat expansions in the C9ORF72 gene might have a distinct subtype of ALS. The C9ORF72-linked form of ALS appears to be earlier onset, about twice as rapidly progressing and may result in certain cognitive and behavioral changes including increased indifference and difficulties in problem solving and making complex decisions.  The disease appears to be distinguished from other forms of ALS using advanced magnetic resonance imaging (MRI). 

The study is one of three studies this month that confirms that repeat expansions in the C9ORF72 gene are the most common cause of inherited forms of ALS, ALS-FTLD and FTLD.

To test or not to test

Most people with C9ORF72-linked ALS identified by the team had a strong history of neurodegenerative disease.  But researchers caution that larger studies are needed to determine whether or not genetic testing is warranted - especially for family members of patients without any signs of either ALS or FTLD. The penetrance is variable.  Nearly one out of every three people with repeat expansions in the C9ORF72 gene (6 out of 20) lived into their 80s and 90s and showed no signs of the disease.  What’s more, researchers remain unsure how many of these repeat sequences in the C9ORF72 gene are needed to trigger the disease.

To further explore the role of the brain in ALS, check out MRI, Make that a double.  To learn more about the emerging role of C9ORF72 in ALS, read Silence is not golden. 

References

Byrne, S. et al. (2012) Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study.  Lancet Neurology 11(3), 232-240. Abstract | Full Text (Subscription Required)

DeJesus-Hernandez, M. et al. (2011) Expanded GGGGCC hexanucleotide repeat in a noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS Neuron 72(2), 245-256. Abstract | Full Text (Subscription Required)

Renton, A.E. et al. (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72(2), 257-268. Abstract | Full Text (Subscription Required)

Hsiung, G.Y. et al. (2012) Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain doi: 10.1093/brain/awr354. Abstract | Full Text (Subscription Required)

Simón-Sánchez J, et al. (2012) The clinical and pathological phenotype of C9orf72 hexanucleotide repeat expansions. Brain doi: 10.1093/brain/awr353. Abstract | Full Text  (Subscription Required)

Whitwell, J.L. & Josephs, K.A. (2012)  Neuroimaging in frontotemporal lobar degeneration—predicting molecular pathology Nature Reviews Neurology doi:10.1038/nrneurol.2012.7.  Abstract | Full Text (Subscription Required)

Further Reading

Andersen, P.M. (2012) Mutation in C9orf72 changes the boundaries of ALS and FTD.  Lancet Neurology 11(3), 205-207.  Full Text (Subscription Required)

Phukan, J., Elamin, M., Bede, P., Jordan, N., Gallagher, L., Byrne, S., Lynch, C., Pender, N. and Hardiman, O. (2012) The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. Journal of Neurology, Neurosurgery and Psychiatry 83, 102-108. Abstract | Full Text (Subscription Required)

Learn more about cognitive and behavioral changes in people with ALS

Mitochondria produce the energy needed to keep muscles healthy and moving. But in people with ALS, these power plants go out of service likely contributing to muscle atrophy and ultimately, paralysis.

Scientists are developing treatments to supe up mitochondria in hopes to keep the energy flowing in the muscles and connecting nerves. One of these emerging medicines, Knopp Biosciences’ dexpramipexole now licensed by Biogen Idec, is gathering steam as a potential ALS treatment strategy. Reporting phase II results last fall, neurologists found that the drug slowed disease progression about 30%.

Some researchers suspect however, that these mitochondrial-targeted medicines may need to do much more than boost energy production to grind ALS to a halt. Even operating at full steam, these power plants may be unable to provide enough energy to keep muscles working because they may not be in the right place to do their job. Scientists are now beginning to understand why these mitochondria might stray, suggesting new strategies to tackle the disease.

Traffic Tie-up

When Massachusetts General Hospital researchers reported the first altered gene, superoxide dismutase 1 (SOD1), linked to ALS in 1993, researchers scrambled to generate and characterize mice with these same mutations in hopes to discover the cause of the disease.

Reporting the first mouse model in 1994, scientists quickly put their finger on a potential contributor to the disease: a power outage in the motor nerves. Researchers, led by Northwestern University School of Medicine neuroscientist Mark Gurney MD, now at Michigan’s Tetra Discovery Partners, reported that the mitochondria swelled up in the motor neurons of SOD mice before showing any signs of ALS suggesting that malfunctions in these intracellular power plants might, in part, lead to the disease.

“But whether [defective] mitochondria were driving the pathology of ALS, that was a question mark,” explains Johns Hopkins University School of Medicine neuroscientist Lee Martin PhD.

In 2004, University of California San Diego researchers led by neuroscientist Don Cleveland PhD found that these misshapen mitochondria appeared at the nerve terminals at about the same time as the muscles became unplugged.

University of California San Diego neuroscientist Christine Vande Velde PhD, now at the University of Montreal, however suspected that more than the breakdown of these power plants could be contributing to ALS. She noticed that these swollen mitochondria accumulate at the neuromuscular junctions in these mice as the disease progressed suggesting that these power plants were unable to travel back towards the cell body to be refurbished or recycled. This so-called retrograde transport of mitochondria is critical to meet energy demands in power-guzzling regions of the motor nerves including the nerve terminals where electric signals are transmitted across the neuromuscular junction which ‘tell’ the muscles to move. If these signaling systems are on the fritz, this too could contribute to muscle weakness and paralysis.

To try and determine whether this impaired mitochondrial dynamics could also be contributing to ALS, Jordi Magrané  PhD and Giovanni Manfredi PhD at Weill Cornell Medical College in New York introduced a system in the late 2000s in which they could fluorescently tag these intracellular power plants in cultured ALS SOD1 mouse spinal cord motor neurons in laboratory dishes and watch them move live in real time under a microscope.

Reporting just last month, the team found that mitochondrial trafficking is indeed affected in the SOD1 mutant motor neurons of the spinal cord. The number of mitochondria that undergo fusion – critical to keep these intracellular power plants in working order – dropped over 50%. And, the movement of mitochondria slowed to a crawl. (Check out the video.) 

Incredibly, the Weill Cornell team found that newly generated power plants constructed in the cell body are already operating at reduced capacity and accumulate at the so-called distal end of the axon, near the nerve terminal. And, the number of mitochondria appear to be reduced at synapse-like structures. These defects appear to be specific to motor neurons. 

“This could be happening in ALS,” says Magrané. 

These findings come at the heels of a study from Vande Velde’s team last summer in which they discovered that mitochondria pile-up in the spinal cord in mutant SOD1 mice during the disease course. 

 

Special delivery.  Mitochondria are pushed down the axons of motor neurons by kinesins along train tracks made of microtubules. The energy these intracellular power plants generate fuels the delivery of electrical signals that ‘tell’ the muscles to move. Adapted from Tsai, M. et al. Molecular Biology of the Cell (2000) 11(6), 2161-2173.

Now, the Weill Cornell team is using the same tools to monitor these intracellular power plants in living ALS mice to determine whether mitochondrial dynamics is indeed defective and contributes to denervation. Looking ahead, the researchers hope to take a look at other mouse models of ALS to determine whether these multi-mitochondrial pile-ups generally contribute to the disease. 

Tracking down the culprit

What causes the transport and recycling machinery to fail in ALS? Researchers remain unsure. One possibility is that the SOD1 enzyme which accumulates during the course of the disease could jam up the works. Reporting last summer, Vande Velde’s team found that these misfolded proteins stick to the surfaces of mitochondria in the spinal cord of ALS mice. This could make these intracellular power plants more difficult to pick up by motor proteins, the neurons’ delivery vehicles, and therefore more difficult to transport.

But new findings from the labs of Hugo Bellen PhD at the Baylor College of Medicine in Texas and Michael Miller PhD at the University of Alabama at Birmingham suggest that there could be an even bigger problem. The systems that keep these power plants upon delivery fixed in position and in tip-top condition could also be out to lunch. 

Reporting last month, the Bellen-Miller team discovered that the putative hormone VAP-B produced by neurons fine-tunes the positions of mitochondria and regulates the energy production in muscles. A hormone that is lacking in all people with ALS tested including those with the sporadic form of the disease.

The Electric Slide

Scientists first stumbled upon a link between VAP-B and ALS in 2004 when geneticist Mayana Zatz PhD and colleagues at São Paulo University in Brazil reported that a mutation in the gene, also known as ALS8, triggered the disease. Reporting in 2008, the Bellen-Miller team discovered that VAP-B appears to be a hormone and that this mutation blocked its secretion. But why a drop in VAP-B levels resulted in ALS remained unclear. 

 

Power punch.  Muscles are packed with mitochondria (arrows) to generate the energy needed for contraction. Here, a section of skeletal muscle is shown. Image: NHBLI, NIH.

To try and get a better idea of why a lack of VAP-B could contribute to ALS, Bellen’s team at Baylor College of Medicine generated fruit flies unable to produce the hormone and watched them develop. The researchers found that very few of these flies survived but the few that did could barely move. Taking a closer look at their muscles, the Bellen team quickly identified the problem. Most of the mitochondria appeared to be broken down. Their muscles just simply did not have enough fuel. 

But, these studies were extremely difficult to do. Too few flies survived for more detailed analysis. So, the researchers turned to Miller’s team at the University of Alabama who were studying the loss of VAP-B in the roundworm. The researchers also noticed that the mitochondria appeared to be malfunctioning. But they also noticed something else. The mitochondria were displaced from the muscle fibers. And, by watching the worms crawl under the microscope, the researchers found out why: these intracellular power plants were not fixed into place. 

VAP-B, however, appears to do a lot more than make sure that mitochondria are next to muscle fibers ready to rock and roll. The hormone appears to regulate the maintenance (fusion) of these power plants and even the amount of fuel produced. Without VAP-B, the mitochondria in these worms’ muscles were operating at as low as 50% capacity. 

”The muscles suffer due to a lack of energy,” explains Bellen. “They produce lactic acid. If you do that chronically, your muscles start to waste.” 

Bellen suspects however, that the loss of this potentially critical hormone could be responsible for a lot more than muscle atrophy in people with ALS. Without mitochondria in the right places in the muscle, calcium that gets generated during movement can build up triggering twitching. And, the drop of a critical protein produced by muscles according to studies in fruit flies could lead to synaptic die-back.

Actin Up

 

Junction box.  Researchers discovered that VAP-B regulates signalling mechanisms which during development, help plug nerves into the right muscles. The team suspects that VAP-B helps enable the movement of these muscles (2) by stabilizing mitochondria (5) at the nerve terminal (1). Image: Wikimedia Commons.

Now, the researchers are looking to see whether a drop in VAP-B levels also results in reduced energy production in motor neurons and a loss of mitochondria from the nerve terminals.

VAP-B appears to be in the right place at the right time to control mitochondrial dynamics in the motor nerves.  The hormone binds to receptors that are also present on the surface of adult nerve cells including motor neurons.

Furthermore, VAP-B appears to be able to do the job.  The hormone controls the position of mitochondria in muscles according to the Bellen-Miller team's findings by regulating the length of the actin-based filaments that anchor them on muscle fibers.  The same kinds of cytoskeletal fibers that are also present at nerve terminals.

“Microtubules form the freeway along which the mitochondria travel to the synapse.   But once they reach the synapse,” explains Bellen,” they need to transfer to another transport system.”

And, that transport system could be controlled by VAP-B.  VAP-B based signaling machanisms could stabilize these intracellular power plants at the nerve terminals – ensuring our muscles have the ability to move.

Looking ahead, the Bellen-Milller team hopes to figure out what triggers the release of VAP-B.  By identifying these regulatory signals, researchers may be able to boost the production of the hormone in people with ALS and in so doing, slow down the disease.

But there may be no need to wait that long.  VAP-B, in its secreted form, might be able to be administered directly to help keep the energy flowing in people with ALS. 

“Maybe there is some therapeutic potential here,” says Miller. “But it is early days.”

References

Han, S.M, Tsuda, H., Yang, Y., Vibbert, J., Cottee, P., Lee, S.J., Winek, J., Haueter, C., Bellen, H.J., Miller, M.A. (2012) Secreted Vap8/als8 major sperm protein domains modulate mitochondrial localization and morphology via growth cone guidance receptors.  Developmental Cell 22, 1-15. Abstract | Full Text  (Subscription Required)

Magrane, J., Sahawneh, M.A., Przedborski, S., Estevez, A.G. and Manfredi, G. (2012) Mitochondrial dynamics and bioenergetics dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons.  Journal of Neuroscience 32(1), 229-242.  Abstract | Full Text  (Subscription Required)

Cudkowicz, M., et al. (2011)  The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis. Nature Medicine 17(12), 1652-1656.  Abstract |  Full Text (Subscription Required)

Vande Velde, C, Garcia, M.L., Yin, X., Trapp, B.D. and Cleveland, D.W. (2004)  The neuroprotective factor Wlds does not attenuate mutant SOD1-mediated motor neuron disease.  NeuroMolecular Medicine 5(3), 193-203. Abstract |  Full Text (Subscription Required)

Magrané, J., Hervias, I., Henning, M.S., Damiano, M., Kawamata, H., and Manfredi G. (2009) Mutant SOD1 in neuronal mitochondria causes toxicity and mitochondrial dynamics abnormalities.  Human Molecular Genetics 18(23), 4552-4564. Abstract |  Full Text

Vande Velde, C., McDonald, K.K., Boukhedimi, Y., McAlonis-Downes, M., Lobsiger, C.S., Bel Hadj, S., Zandona A., Julien, J.P., Shah, S.B. and Cleveland, D.W. (2011) Misfolded SOD1 associated with motor neuron mitochondria alters mitochondrial shape and distribution prior to clinical onset.  PLoS One 6(7), e22031. Abstract |  Full Text

Nishimura, A.L., Mitne-Neto, M., Silva, H.C., Oliveira, J.R., Vainzof, M. and Zatz, M. (2004)  A novel locus for late onset amyotrophic lateral sclerosis/motor neurone disease variant at 20q13.  Journal of Medical Genetics 41(4), 315-320. Abstract |  Full Text

Tsuda, H et al. (2008) The amyotrophic lateral sclerosis 8 protein VAPB is cleaved, secreted, and acts as a ligand for Eph receptors.  Cell 133(6), 963-977. Abstract |  Full Text

Goold, C.P. and Davis, G.W. (2007)  The BMP ligand Gbb gates the expression of synaptic homeostasis independent of synaptic growth control. Neuron 56(1), 109-123. Abstract |  Full Text

Ratnaparkhi, A., Lawless, G.M., Schweizer, F.E., Golshani, P. and Jackson, G.R. (2008) A Drosophila model of ALS: human ALS-associated mutation in VAP33A suggests a dominant negative mechanism. PLoS One 3(6), e2334. Abstract |  Full Text 

 

The NeuRX Diaphragm Pacing System. Image: Synapse Biomedical.

Researchers in the UK will soon be putting the NeuRX diaphragm pacing system (DPS) to the test to determine whether the device in combination with non-invasive ventilation (NIV) improves the quality of life and extends survival of people with ALS experiencing respiratory weakness. The clinical trial, known as Diaphragm Pacing In Motor Neuron Disease (DiPALS), will be conducted at 10 National Health Service (NHS) hospitals in the UK. Trial participants will receive either NIV or NIV and be implanted with the NeuRX DPS.  108 people with ALS are expected to enroll.  The trial is expected to be completed in 2014.

To read more about the NeuRx diaphragm pacer and how the device might benefit people with ALS, read our recent feature DPS Sleep.

Further Reading

Marion, D.W. (2011) Diaphragm Pacing.  UpToDate.  Excerpt |  Full Text (Subscription Required)  

Patient Resources

Diaphragm Pacing in Motor Neuron Disease (DiPALS) Study. Contact | ALS TDI  |  Website 

Microglia produce toxic substances that contribute to the inflammation of the motor nerves.   But these watch dogs of the brain and spinal cord might not be bad to their cytoskeletal  'bones', according to a study published this week.   The research team led by the University of Freiburg’s Knut Biber PhD discovered that resting microglia might actually help keep neurodegeneration in check by protecting neurons from death by glutamate (a.k.a glutamate-induced excitotoxicity).  The study focused on cultured nerve cells derived from the hippocampal region of healthy mouse brain.

Looking towards the clinic, this study suggests that quieting these angry watchdogs may be better than putting them to sleep to combat inflammation in people with ALS.  Soothing strategies currently in the pipeline include Neuraltus Pharamaceuticals' NP001.

To learn more about therapies researchers are developing to combat cytotoxic microglia in ALS, listen to our recent podcast with Methodist Neurological Institute’s Stan Appel MD, Symphony in M.

Reference

Vinet, J., van Weering, H.R., Heinrich, A., Kalin, R.E., Wegner, A., Brouwer, N., Heppner, F.L., van Rooijen, N., Boddeke, H.W. and Biber K. (2012). Neuroprotective function for ramified microglia in hippocampal excitotoxicity. Journal of Neuroinflammation 9(1), 27. Abstract | Full Text  

Further Reading

Appel, S.H., Beers, D.R, and Henkel, J.S. (2008). T cell-microglial dialogue in Parkinson's disease and amyotrophic lateral sclerosis: are we listening? Trends In Immunology, 31(1), 7-17.  Abstract | Full Text (Subscription Required)