Staying connected. GSK's ozanezumab may enable motor neuronal axons damaged by ALS to be repaired and reconnected to muscle fibers by mopping up Nogo-A (an axon growth blocker) in the surrounding debris. Image: JieFei Yang PhD, Salk Institute.

Motor neurons signal our muscles to move. But in people with ALS, the neuromuscular junctions that transmit these electrical messages crumble leading to muscle weakness, paralysis and respiratory failure.

Researchers are working hard to develop medicines that protect these structures in hopes to slow or stop the progression of disease.  One of these medicines, GlaxoSmithKline’s ozanezumab (GSK1223249), hopes to do just that by helping keep the motor nerves and muscle fibers connected.

Ozanezumab is currently being tested in the clinic. A 48 week phase II trial is ongoing.  Nearly 300 people with ALS are expected to participate worldwide.

ALS Today’s Michelle Pflumm PhD talked to participating neurologist Pierre-François Pradat MD PhD of the Hôpital de la Pitié-Salpétrière in Paris to learn more about ozanezumab and its potential to treat ALS going forward.

To find out about other emerging strategies to help keep muscles moving, check out CK-357, helping pALS live strong? and Exercise: stretching the limits of ALS care. 

Patient Resources

Study of Ozanezumab in the Treatment of Amyotrophic Lateral Sclerosis  Contact  ALS TDI  Website

References

Pradat, P.F. et al. (2011) Abnormalities of satellite cells function in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis 12(4), 264-271.  Abstract  |  Full Text  (Subscription Required)

Pradat, P.F. et al. (2007) Muscle Nogo-A expression is a prognostic marker in lower motor neuron syndromes. Annals of Neurology 62(1), 15-20.  Abstract  |  Full Text  (Subscription Required)

Jokic, N, Gonzalez de Aguilar, JL, Dimou, L, Lin, S, Fergani, A, Ruegg, MA, Schwab, ME, Dupuis, L and Loeffler, J.P. (2006) The neurite outgrowth inhibitor Nogo-A promotes denervation in an amyotrophic lateral sclerosis model.  EMBO Reports 7(11), 1162-1167.  Abstract  |  Full Text

Jokic, N. et al.(2005) Nogo expression in muscle correlates with amyotrophic lateral sclerosis severity. Annals of Neurology 57(4), 553-556. Abstract  |Full Text  (Subscription Required)

Further Reading

Krakora, D., Macrander, C. and Suzuki, M. (2012) Neuromuscular junction protection for the potential treatment of amyotrophic lateral sclerosis.  Neurology Research International 2012, 379657. Abstract  |  Full Text

 

Muscles cramping your style? A group of US neuromuscular disease specialists are evaluating mexiletine as a potential treatment option for muscle cramps. Image: Pacific Northwest Health & Safety Center, University of Washington.

More than 50% of people with ALS experience pain. Their discomfort, however, is underreported, undertreated and often ignored by health teams.  Few pain relievers except Advil® and Aleve® are typically prescribed to people with ALS – particularly at early stages of the disease.

No pain medication is considered standard clinical practice for people with ALS. 

A growing number of neurologists are working hard to identify more effective pain relievers in hopes to improve the quality of life of their ALS patients.  One such medicine, mexiletine, is emerging as potential treatment option for muscle cramps – a key cause of physical discomfort in people with the disease.

A phase IV clinical trial is scheduled to begin in April 2013.

“We know the drug. It’s pretty safe and available,” explains University of California-Davis (UCD) School of Medicine‘s Bjorn Oskarsson MD, principle investigator of the study.  “And, we don’t have a good alternative today.”

For decades, people with a number of neurological and neuromuscular diseases reached for quinine (the key ingredient in tonic water) – particularly before going to bed. But these tablets are no longer recommended by the FDA for routine use due to concerns of potentially fatal blood and heart complications.

In recent years, University of California-Davis School of Medicine's Bjorn Oskarsson MD turned to mexiletine as a potential alternative to treat muscle cramps in people with ALS. The drug quiets down overactive neuronal sodium channels – the prime suspect behind cramps in people with the disease.

 

Symptoms reducer? A growing number of medicines are being explored to improve the quality of life for people with ALS.

Mexiletine is one of growing number of medicines that aims to improve quality of life for people with ALS.

“If we can find treatments to help with the symptoms,” says University of Missouri School of Medicine’s Richard Barohn MD, “I think that’s a great thing.”

Now, US physicians are gearing up to put mexiletine to the test in people with ALS. The phase IV randomized placebo-controlled study is to take place in California. Participating Pacific ALS Consortium (PAC-10) sites include University of California Davis School of Medicine in Sacramento. 30 people with ALS are expected to participate.

The clinical trial is 1 of 2 studies in the US that aims to determine whether the FDA-approved heart medicine can relieve muscle cramps in people with ALS.

"We have a really good safety profile regarding this medicine," says neuromuscular disease specialist Michael Weiss MD, principal investigator of the concurrent Northeast ALS Consortium clinical trial.

Mexiletine is 1 of at least 5 existing medicines being evaluated to relieve key symptoms of the disease. “We’re not curing ALS,” says Oskarsson.  “This is the kind of treatment that might help people live better with their ALS.”

To learn more about mexiletine and its potential benefits for people with ALS, check out our interactive feature Mexiletine: channeling ALS?

Patient Resources

Mexiletine for the treatment of muscle cramps in ALS.  Contact | ALS TDI | Website 

A safety and tolerability study of mexiletine in patients with sporadic ALS.  Contact | ALS TDI | Website 

References

Rivera, I., Ajroud-Driss, S., Casey, P., Heller, S., Allen, J., Siddique, T. and Sufit, R. (2013) Prevalence and characteristics of pain in early and late stages of ALS.  Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration Journal doi:10.3109/21678421.2012.751614.  Abstract  |  Full Text (Subscription Required)

Chiò, A., Canosa, A., Gallo, S., Moglia, C., Ilardi, A., Cammarosano, S., Papurello, D. and Calvo, A (2012) Pain in amyotrophic lateral sclerosis: a population-based controlled study. European Journal of Neurology 19(4),  551-555.  Abstract  | Full Text (Subscription Required)

Baldinger, R., Katzberg, H.D. and Weber M (2012) Treatment for cramps in amyotrophic lateral sclerosis/motor neuron disease.  Cochrane Database of Systematic Reviews, doi: 10.1002/14651858.CD004157.pub2.  Abstract  |  Full Text (Subscription Required)

Brettschneider, J., Kurent, J., Ludolph, A. and Mitchell, J.D. (2010) Drug therapy for pain in amyotrophic lateral sclerosis or motor neuron disease. Cochrane Database of Systematic Reviews, doi: 10.1002/14651858.CD005226.pub2.  Abstract  |  Full Text (Subscription Required)

Further Reading

Handy CR, Krudy C, Boulis N, Federici T. (2011) Pain in amyotrophic lateral sclerosis: a neglected aspect of disease.  Neurology Research International 2011, 403808.  Abstract  |  Full Text

 

Calming ALS nerves Mexiletine may help protect the motor nerves from further damage by reducing the overactivity of sodium channels (blue) snaking through the CNS. Courtesy of Wellcome Images.

New medicines can take more than a decade to go from the laboratory to the clinic. But with many of their ALS patients facing 2-5 years to live, clinicians are rethinking the way that potential medicines are being pushed forward in the clinic. Adaptive clinical trial designs according to some experts might enable drugs to be evaluated more rapidly. And, futility studies may allow ineffective and unsafe medicines to be more quickly discarded.

Some researchers, however, hope to bring potentially life-changing treatments to people with ALS even faster by dusting off existing FDA-approved drugs from pharmacy shelves which target emerging key mechanisms of the disease.

One of these medicines, mexiletine, may help reduce the overactivity (hyperexcitability) of certain neurons in people with ALS, a potentially early step in the disease.  The drug, suspect researchers, may therefore reduce further injury to the motor nerves – slowing the progression of the disease.

”Mexiletine could be of benefit in ALS,” says University of Washington School of Medicine neuromuscular disease specialist Michael Weiss MD, principal investigator of the study.  “Hyperexcitability could be a very early event in the neurodegenerative process.”

The phase II clinical trial is scheduled to begin sometime in early 2013.

Check out our podcast with UW neurologist Michael Weiss MD to learn more about mexiletine and its potential benefits for people with ALS.

Clinicians first looked to mexiletine in the early 1990s to reduce muscle stiffness in people with a rare group of muscle diseases called myotonias.  The drug, originally developed to regulate heart rhythms, is thought to shut the gate of inappropriately activated sodium channels - helping muscles relax more easily.

Mexiletine, recently put to the test in people with non-dystrophic myotonias, appears to reduce key signs of “myotonia” including muscle stiffness and muscle pain.  The drug is quickly becoming routine practice for myotonia in people with these muscle diseases.

“We showed that mexiletine worked.  It’s a really big deal,” says University of Kansas Medical Center neuromuscular disease specialist Richard Barohn MD, leader of the study.

Mexiletine is now being evaluated as a potential treatment for muscle cramps in a growing number of conditions– including in people with ALS.

“We think the large [part of the] problem with muscle cramps is these persistent sodium channels,” explains University of California - Davis School of Medicine neurologist Bjorn Oskarsson MD, principal investigator of the study.  “The axons are not working right.”

Out of hyperdrive?

University of Massachusetts neurologist Robert Brown MD however suspects that mexiletine might do much more for people with ALS.  The drug might reduce the overactivity of sodium channels on certain neurons in the brain and spinal cord – a potential cause or contributor to the damage that fuels the progression of ALS. The daily treatment of mexiletine according to Brown significantly extends the survival of a mouse model of the disease.

This overactivity, know as hyperexcitability, is suspected to be an early step in the disease according to studies led by King's College London's Kerry Mills PhD FRCP and Neuroscience Research Australia’s Steve Vucic PhD.  Sodium channels that decorate certain neurons of the motor regions of the brain appear to be overactive in people with ALS. And, these changes may occur before the onset of symptoms according to a small study of people at high risk of developing the familial form of the disease.

Mexiletine therefore might not only protect the motor nerves from further damage; the drug might slow ALS even earlier in the disease course.

Now, US neurologists are gearing up to put mexiletine to the test in people with ALS to determine whether the drug can indeed slow down the disease. 

The 16 week phase II clinical trial will take place at 10 Northeast ALS Consortium (NEALS) sites in the US including the University of Washington School of Medicine, University of Kansas Medical Center and Penn State University School of Medicine.

The main goal is to evaluate the safety and tolerability of mexiletine in people with ALS.  Other measures include functional abilities (ALS FRS) and the frequency and severity of muscle cramps. 60 people with ALS are expected to participate.

“Mexiletine is a drug we know a fair amount about,” says University of Washington neuromuscular disease specialist Michael Weiss MD.  “It’s a pretty safe medicine.  It’s been FDA-approved for almost two decades.”

Patient Resources

A safety and tolerability study of mexiletine in patients with sporadic ALS.  Contact | ALS TDI | Website 

Mexiletine for the treatment of muscle cramps in ALS.  Contact | ALS TDI | Website 

References

Vucic, S and Kiernan, M.C. (2010) Upregulation of persistent sodium conductances in familial ALS. Journal of Neurology, Neurosurgery and Psychiatry 81(2), 222-227. Abstract | Full Text (Subscription Required)

Vucic, S., Nicholson, G.A. and Kiernan, M.C. (2008) Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. Brain 131, 1540-1550.  Abstract | Full Text

Mills, K.R. and Nithi, K.A. (1997) Corticomotor threshold is reduced in early sporadic amyotrophic lateral sclerosis.  Muscle and Nerve 20(9), 1137-1141. Abstract | Full Text (Subscription Required)

Kwieciński, H., Ryniewicz, B. and Ostrzycki, A. (1992)  Treatment of myotonia with antiarrhythmic drugs. Acta Neurologica Scandinavica 86(4), 371-375. Abstract | Full Text (Subscription Required)

Further reading

Vucic, S., Ziemann, U., Eisen, A., Hallett, M. and Kiernan, M.C. (2012) Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights. Journal of Neurology, Neurosurgery and Psychiatry doi:10.1136/jnnp2012-304019 Abstract | Full Text  (Subscription Required)

Statland, J.M. et al. (2012) Mexiletine for symptoms and signs of myotonia in nondystrophic myotonia: a randomized controlled trial. Journal of the American Medical Association 308(13), 1357-1365. Abstract |  Full Text (Subscription Required)

Kanai, K., Kuwabara, S., Arai, K., Sung, J.Y., Ogawara, K. and Hattori, T. (2003) Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment. Brain 126, 965-973.  Abstract | Full Text

 

Power up? Tirasemtiv may increase the power generated from fast skeletal muscle according to SUNY Medicine's Jeremy Shefner MD. Courtesy of Nature Publishing Group. All Rights Reserved.

Cytokinetics’ potential muscle booster tirasemtiv (CK-357) appears to be safe and tolerated.  But riluzole dosages need to be reduced 50% due to the drug’s ability to block riluzole breakdown according to phase IIa clinical trial results presented by State University of New York Medical University’s Jeremy Shefner MD PhD. “The evidence thus far supports the further evaluation of tirasemtiv,” says Shefner.

A phase IIB 20-week randomized, double-blind placebo-controlled clinical trial is now recruiting.  400 people are expected to participate.  Sites include clinics in US and Canada.

To learn more about tirasemtiv, read CK-357, helping pALS live strong? To find out about other emerging treatments for ALS, check out our full International ALS/MND Symposium meeting report ALS Trials and Tribulations.

Alterations in nearly 20 genes have been linked to ALS.  But according to a growing number of studies, chemical changes to the genome might also be contributing to the disease.

Scientists are now looking to emerging cancer medicines in hopes to reset many of these so-called epigenetic switches in people with ALS.  But the drugs tested to date appear to be ineffective in the clinic. Some researchers suspect that these medicines simply cannot be given at high enough doses to be effective.  Their amounts strictly limited due to potentially harmful side effects.

Now, a growing number of scientists are developing so-called “next-generation” histone deacetylase (HDAC) inhibitors in hopes to create safe and more effective epigenetic medicines.  More selective drugs are currently being tested in the cancer clinic. And, central nervous system (CNS)-available medicines are being developed for the treatment of neurodegenerative diseases.

This month, experts met up at Discovery on Target 2012 to share the latest epigenetic therapeutic strategies and their potential in the clinic going forward.

The meeting, which took place on October 1-2 2012 in Boston, highlighted emerging medicines for a wide-range of medical conditions including diabetes, sickle cell anemia and cardiovascular disease. 

 

Overcoming obstacles Researchers first looked at general histone deacetylase inhibitors including trichostatin A in hopes to boost levels of neuroprotective substances in people with ALS. Image: Riken Institute, Japan.

Researchers first looked to epigenetic strategies in the late 1970s to treat cancer – hoping to stop the disease in its tracks by switching on tumor suppressive and tumor-killing genes. General HDAC-targeting medicines appeared promising in preclinical studies.  But concerns of heart problems slowed their entrance into the clinic. Only two HDAC blockers are currently FDA-approved for use and only for the treatment of a rare form of the disease. 

“The field is littered with failures,” says oncologist Kapil Dhingra MBBS. “Let’s call it a failure of blind enthusiasm.”

The field, however, appears to be turning a corner according to Dhingra, former head of Roche Oncology.  A growing number of emerging HDAC-targeting medicines appear to be safe and exhibit “acceptable” toxicity profiles.  But drug developers still remain in “phase II exploration mode” – looking largely for optimal combinations with other medicines to treat specific forms of the disease.

For researchers developing treatments for neurodegenerative conditions, however, the generation of safe and effective medicines are not the only challenges according to Repligen’s Senior Director of Preclinical Development Vincent Jacques PhD.  These medicines need to be efficiently and effectively delivered into the central nervous system. “Most histone deacetylase inhibitors on the market today do not cross the blood brain barrier,” explains Jacques.

To meet these challenges, a growing number of scientists are looking to specific structural classes of histone deacetylase inhibitors such as benzamides which appear to be relatively safe, tolerable and can get into the brain and spinal cord. 

Broad Institute's Stanley Center Director of Medicinal Chemistry Edward Holson PhD introduced drugs that appear to be primarily targeting HDAC3 that might be helpful in Alzheimer’s disease according to preliminary preclinical studies presented at DOT 12.  And, Repligen’s Vincent Jacques PhD presented a clinical update on their lead candidate, RG2833, targeting HDAC1 and HDAC2 which currently is in phase I clinical trials for Friedrich’s ataxia. Whether a next-generation pan or selective HDAC-targeting medicine is the best choice is an open question and remains hotly debated in the field.

No study published to date has evaluated the benefits of any of these emerging medicines in ALS.

 

Tubastatin A Researchers are developing derivatives of HDAC6 blocker tubastatin A in hopes to generate medicines that help  prevent transplant rejection and/or complications. 

Protect and serve

Researchers first looked toward epigenetic medicines as a potential treatment for ALS in hopes to boost the production of potentially ALS-slowing neuroprotective substances. But a growing number of scientific studies suggest that inhibiting these histone-modifying enzymes might do much more to help fight the disease. 

Treatment with HDAC6 blockers might “wake up” certain populations of regulatory T cells (Tregs), according to Children’s Hospital of Philadelphia (CHOP) organ transplant pathologist Wayne Hancock MBBS PhD, reducing inflammation. Elimination of HDAC6 appears to prevent transplant arteriosclerosis, a major life-threatening complication of heart transplants that occurs post-surgery according to preclinical studies Hancock presented at DOT12. What’s more, treatment with HDAC6 inhibitors appears to boost Treg function and protect mouse models against heart transplant rejection. Now, studies are underway at CHOP to determine if these same medicines can also help prevent heart transplant complications.

“These are the cells that keep you on the straight and narrow,” explains Hancock. 

Including potentially people with ALS.  Recent studies from Houston’s Methodist Hospital neurologist Stan Appel MD found that Tregs appear to help protect the motor nerves from destruction – reducing microglial-based neuroinflammation and extending survival in mouse models of disease.  What’s more, the larger the numbers of circulating Tregs in people with ALS, the lower the progression rate of their disease according to a 2011 study. Treating people with ALS with HDAC6-targeting medicines therefore might boost the abilities of these cells to help keep neuroinflammation in check and thereby slow down the disease.

But according to Duke University School of Medicine research scientist Tso-Pang Yao PhD, the generation of HDAC4 inhibitors still remains a high priority – particularly for those developing treatment strategies for ALS.  The deacetylating enzyme appears to be turned up in ALS and activates the production of proteins in skeletal muscle - resulting in muscle atrophy according to his studies. Potential HDAC4 blockers therefore might boost muscle strength in people with the disease.

To learn more about emerging medicines that may help reset chemical switches in people with ALS, check out our recent feature: Breaking the code of silence in ALS.  To find out about the emerging role of T cells in ALS, tune into our podcast Symphony in M with Houston Methodist Hospital neurologist Stan Appel MD.

References

Beier, U.H., Wang, L., Han, R., Akimova, T., Liu, Y., Hancock, W.W. Histone deacetylases 6 and 9 and sirtuin-1 control Foxp3+ regulatory T cell function through shared and isoform-specific mechanisms. Science Signaling 5(229), ra45. Abstract | Full Text (Subscription Required)

Kalin, J.H., Butler, K.V., Akimova, T., Hancock, W.W. and Kozikowski, A.P. (2012) Second-generation histone deacetylase 6 inhibitors enhance the immunosuppressive effects of Foxp3+ T-regulatory cells. Journal of Medicinal Chemistry 55(2), 639-651. Abstract | Full Text

de Zoeten, E.F. et al. (2011) Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp3(+) T-regulatory cells.  Molecular and Cell Biology 31(10), 2066-2078. Abstract | Full Text

Beers, D.R., Henkel, J.S., Zhao, W., Wang, J., Huang, A., Wen, S., Liao, B. and Appel, S.H. (2011) Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain 134, 1293-1314. Abstract | Full Text

Zhao W, Beers DR, Liao B, Henkel JS, Appel SH. (2012) Regulatory T lymphocytes from ALS mice suppress microglia and effector T lymphocytes through different cytokine-mediated mechanisms. Neurobiology of Disease 48(3), 418-428. Abstract | Full Text (Subscription Required)

Choi, M.C., Cohen, T.J., Barrientos, T., Wang, B., Li, M., Simmons, B.J., Yang, J.S., Cox, G.A., Zhao, Y. and Yao, T.P. (2012) A direct HDAC4-MAP kinase crosstalk activates muscle atrophy program. Molecular Cell 47(1), 122-132. Abstract | Full Text (Subscription Required)

Cohen, T.J., Waddell, D.S., Barrientos, T., Lu, Z., Feng, G., Cox, G.A., Bodine, S.C. and Yao, T.P. The histone deacetylase HDAC4 connects neural activity to muscle transcriptional reprogramming. Journal of Biological Chemistry 282(46), 33752-33759. Abstract | Full Text

Further Reading

Kazantsev, A.G. and Thompson, L.M. (2008) Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nature Reviews Drug Discovery 7(10): 854-868. 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.  These so-called fast skeletal muscles are 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 

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