Categories: Podcast

Charting the course of ALS

clock January 31, 2014

ALS MND FTD FTLD C9orf72 prion spread TDP-43 TDP43

 

Follow the TDP-43 Road The spread of key proteins (red) between neurons in the brain and the spinal cord may in part explain the regional progression of the disease. Adapted from Braak, H. et al. (2013). Courtesy of Nature Publishing Group.

ALS occurs due to a progressive loss of motor neurons – the cells that enable muscles to move. One arm or leg may often be at first affected. But over time, the disease spreads throughout the body leading to paralysis and respiratory failure.

Researchers across the globe are working hard to understand how ALS spreads in hopes to develop more effective treatment strategies that stop the disease in its tracks. And, keep people with ALS moving.

One approach, led by University of Pennsylvania School Of Medicine’s John Trojanowski MD PhD, aims to retrace the ‘steps’ of ALS by tracking TDP-43, a protein that accumulates in motor neurons in more than 90% of people with the disease.

The strategy, pioneered by Universitätsklinikum Ulm neuroanatomist Heiko Braak MD in Germany, has provided insights into a growing number of neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease and most recently, frontotemporal dementia (FTD).

Now, the US-German team reports that ALS may travel through key regions of the brain using the axons that connect them. And, classifies the progression of the disease, based on the trajectory of TDP-43, into four distinct stages.

The results may enable clinicians in the future to predict the course of ALS in their patients.  And, inform their care.

ALS Today’s Michelle Pflumm PhD talked with University of Pennsylvania School of Medicine’s Virginia Lee PhD and John Trojanowski MD PhD about their latest findings and their potential implications for people with ALS going forward.

***

To find out about emerging methods to track ALS in people with the disease, check out our American Association for the Advancement of Science (AAAS) 2013 meeting report A Brave New World.

References

Brettschneider, J. et al. (2013) Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Annals of Neurology 74(1), 20-38.  Abstract  |  Full Text  

Braak, H., Brettschneider, J., Ludolph, A.C., Lee, V.M., Trojanowski, J.Q. and Del Tredici, K. (2013)  Amyotrophic lateral sclerosis-a model of corticofugal axonal spread. Nature Reviews Neurology 9(12), 708-714.  Abstract  |  Full Text   (Subscription Required) 

Further Reading

Ravits, J.M. and La Spada, A.R. (2009) ALS motor phenotype heterogeneity, focality and spread. Neurology 73(10), 805-811.  Abstract  |  Full Text  

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Categories: Podcast

A Go For anti-Nogo-A

clock April 9, 2013

neuromuscular junction NMJ NOGO-A ALS

 

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

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Categories: Podcast

Gilenya, giving ALS the fingo?

clock February 12, 2013

T cell infiltration costimulatory pathway inflammation CD40L ALS MND

 

T mobile Certain cytotoxic T cells infiltrate the brain and spinal cord in people with ALS - potentially contributing to disease progression. Image: Jennifer Fairman for ALS TDI.

T cells help keep our bodies free from infection. But in people with ALS, some of these white blood cells appear to enter attack mode. And, unleash a storm of toxic substances that damage the motor nerves - fueling the progression of the disease.

Researchers hope to develop medicines that protect the motor nerves in people with ALS by keeping these troublesome T cells out of the nervous system. One of these emerging treatment strategies, fingolimod, locks them up in the lymph nodes.

The FDA-approved multiple sclerosis medicine, marketed by Novartis under the name Gilenya, is one of a growing number of immune system-based treatment strategies that hope to slow ALS by reducing inflammation. Others include Neuraltus Pharmaceuticals' NP001, Roche’s Actemra (tocilizumab) and UCB’s CDP7657 (anti-CD40L Fab).

The phase IIA clinical trial is expected to begin in the spring of 2013.

ALS Today’s Michelle Pflumm PhD talked to ALS TDI CEO and Chief Scientific Officer Steve Perrin PhD to learn more about Gilenya, other emerging immunomodulators for ALS and their potential to treat the disease going forward.

 

To learn more about emerging role of the immune system in ALS and potential treatment strategies for the disease, check out NP001, a quiet riot for ALS?

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Categories: Podcast

NP001, a quiet riot for ALS?

clock December 17, 2012

antisense oligonucleotides ASO RNAseH ALS

CNS Invaders. In people with ALS, increased numbers of cytotoxic macrophages (pictured above) might enter the central nervous system and damage the motor nerves - contributing to disease progression. Image: MRC National Institute of Medical Research.

Macrophages help keep our tissues healthy and free from infection.  But in people with ALS, increased numbers of these immune cells may go into attack mode and enter the central nervous system– spewing toxic cytokines on the motor nerves.

Scientists are working hard to develop treatments that quiet down these cellular attack dogs in hopes to slow down ALS. One of these emerging medicines, Neuraltus Pharmaceutical’s NP001, is soon to be evaluated in the clinic.  The phase III clinical trial is scheduled to launch in the second half of 2013.

At the 2012 International Symposium on ALS/MND in Chicago, ALS Today’s Michelle Pflumm PhD talked to California Pacific Medical Center’s Forbes Norris ALS Clinic Director Robert Miller MD to learn more about NP001 and its potential to treat ALS going forward.

 

To learn more about other emerging medicines for ALS, check out the end of this podcast and our ALS/MND 2012 meeting report ALS Clinical Trials and Tribulations.

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Categories: Podcast

ALS, dressed to the C9s

clock October 29, 2012

antisense oligonucleotides ASO RNAseH ALS

Search and destroy. Antisense oligonucleotides directed against the repeat expanded form of C9ORF72 RNA bind these potentially toxic molecules - tagging them for destruction. Image: Courtesy of Rockefeller University Press.

Repeat expansions in the C9ORF72 gene appear to be the most common cause of ALS identified to date – potentially explaining nearly 40% of cases of the inherited form of the disease.  Researchers, however, remain unsure why these repeat sequences within the first intron of the gene trigger ALS. 

Some scientists suspect that the repeat expanded C9ORF72 RNA might act as a sponge – soaking up transcription factors in motor neurons needed to keep these muscle-moving cells healthy.  But the loss of function of C9ORF72 alone could also potentially result in the disease.

Researchers hope to distinguish these possibilities by developing human induced pluripotent stem cell (iPS) and mouse models of C9ORF72-linked ALS and studying the underlying mechanism of the disease.

A growing number of scientists, however, are hedging their bets by developing antisense-based strategies that reduce these potentially toxic RNAs in hopes to create a treatment more quickly for this form of ALS. These small oligonucleotides, called gapmers, bind specifically to these repeat expanded RNA molecules – intracellularly targeting them for destruction.

ALS Today‘s Michelle Pflumm PhD talked to Johns Hopkins University School of Medicine neurologist Jeff Rothstein MD PhD about C9ORF72 and potential treatments for this form of ALS going forward.

To learn more about C9ORF72, check out our interactive timeline.

 

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Categories: From The Bench , Podcast

ALS: Much Ado About Oligodendrocytes

clock August 20, 2012

oligodendrocyte oligodendroglia myelin motor neuron ALS

 

Plan B. Oligodendrocytes (green) appear to deliver energy-rich metabolites to motor neurons (purple) during periods of high energy usage. Image: Alan Hoofring, Medical Arts Design Section, National Institutes of Health.

Oligodendrocytes are the tuners of the central nervous system, which busily insulate the nerves' axons to optimize the performance of the brain and spinal cord.

But when energy levels drop, these cellular handymen take on a second job. Oligodendrocytes supply nerve cells with energy-rich metabolites such as lactate to help keep the power on. 

Recent studies suggest however that these intercellular deliveries might be interrupted in people with ALS.  And, this break in the metabolic supply chain may contribute to the onset and progression of the disease.

ALS Today's Michelle Pflumm PhD talked to Max Planck Institute of Experimental Medicine neuroscientist Klaus-Armin Nave PhD about oligodendrocytes, their emerging role in ALS and potential treatment strategies going forward.

 

To learn more, check out our watchlist: The oligodendrocyte, a new player in ALS?

References

Fünfschilling, U. et al. (2012) Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485, 517-521. Abstract  |  Full Text

Lee, Y. et al. (2012) Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature, doi:10.1038/nature11314.  Abstract  |  Full Text

Kang, S.H., Fukaya, M., Yang, J.K., Rothstein, J.D. and Bergles DE. (2010)  NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration. Neuron 68(4), 668-681.  Abstract  |  Full Text

Griffiths, I. et al. (1998)  Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280, 1610-1613. Abstract  |  Full Text   

Further Reading

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


 

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Categories: Podcast , Postcards

TROPALS, Circle In the Sand

clock June 21, 2012

 

Postcard from Burkina FasoThere are only 5 neurologists in Burkina Faso.  But that doesn’t stop Athanase Millogo MD from making a difference for people with ALS beyond his nation’s borders. Photo courtesy of Athanase Millogo MD.  All rights reserved.

With the opening of dozens of specialized ALS clinics and the establishment of multipractice care programs, nearly 1 out of every 5 people with ALS in the US now lives at least 5 years after being diagnosed with the disease.  And, nearly 1 out of 10 survives more than a decade.

But in Africa, ALS is instead a neglected non-communicable disease.  Few general practitioners recognize motor neuron disorders.  And, most people cling to traditional healing practices resulting in treatments being prescribed according to a recent analysis as much as 4.5 years after the first signs of the disease.

A group of neurologists, called TROPALS, however is determined to turn things around for people with ALS in Africa.  The team has launched an unprecedented multicenter longitudinal study to describe ALS in Africa.  And, at the same time identify key challenges facing these populations in hopes to ultimately to develop interventions to improve their quality of life.

“We are working for the patients,” explains Athanase Millogo MD, head of the Department of Medicine, Bobo-Dialousso Teaching Hospital in Burkina Faso. “We are not sitting in our offices making computations.  We hope to improve the outcome of people with the disease.”

Reference

Marin, B. et al. (2012) Juvenile and adult-onset ALS/MND among Africans: incidence, phenotype, survival: a review. Amyotrophic Lateral Sclerosis 13(3), 276-283.  AbstractFull Text  (Subscription Required)

Researcher Resources

Etude Epidémiologique de la Sclérose Latérale Amyotrophique sous les Tropiques (TROPALS) Email | Website

Study of Amyotrophic Lateral Sclerosis Under the Tropics (TROPALS) Email | Website

 

 

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Categories: Podcast

Symphony in M

clock December 16, 2011



Stakeout. A microglial cell looks out for pathogenic intruders in the mouse brain. Image: Rosa Paolicelli, EMBL Monterotondo.

Since Jean-Martin Charcot MD described ALS during one of his Tuesday lectures at Paris' Salpêtrière Hospital in 1874, researchers around the world have looked hard at disease-ravaged motor neurons to try and figure out why these neurons fail in people with ALS. But in the 1980s, neurologist Stanley Appel MD, now at Methodist Neurological Institute in Houston, proposed that ALS was much more than a motor neuron disease. He suggested based on taking a look at spinal cord tissue from patients that the inappropriate activation of microglia and astrocytes – the primary immune cells of the central nervous system (CNS) – lead to a storm of cytotoxic substances that ultimately destroys the motor nervesResearch studies since then suggest that at least in mice, an orchestrated dialogue between microglia and motor neurons drives the progression of the disease.

ALS Today’s Michelle Pflumm PhD talked to Stanley Appel MD about the emerging role of cytotoxic microglia in ALS and potential treatment strategies to combat them looking forward.

 



The many insults to motor neuron injury. Misfolded proteins such as mutant superoxide dismutase 1 (SOD1) in people with ALS may lead to the deterioration of the motor nerves in part by triggering inflammation.  Instigated in part by microglia that are activated either by misfolded proteins directly (E) or indirectly through distress signals (B), microglia produce toxic substances (F) that injure and ultimately destroy the motor nerves.  Adapted from Ilieva, H. et al. (2009) Journal of Cell Biology.

References

Appel, S.H., Stockton-Appel, V., Stewart, S.S., and Kerman R.H. (1986) Amyotrophic lateral sclerosis. Associated clinical disorders and immunological evaluations. Archives of Neurology, 43(3), 234-238. Abstract  |  Full Text (Subscription Required)

Engelhardt, J.I., and Appel, S.H. (1990) IgG Reactivity in the Spinal Cord and Motor Cortex in Amyotrophic Lateral Sclerosis. Archives of Neurology, 47(11), 1210-1216. Abstract | Full Text (Subscription Required)

Boillée, S., Yamanaka, K., Lobsiger, C.S., Copeland, N.G., Jenkins, N.A., Kassiotis, G., Kollias, G., and Cleveland, D.W. (2011) Onset and progression in inherited ALS determined by motor neurons and microglia. Science, 312(5778), 1389-1392. Abstract | Full Text (Subscription Required)

Beers, D.R., Henkel, J.S., Xiao, Q., Zhao, W., Wang, J., Yen, A.A., Siklos, L., McKercher, S.R., and Appel, S.H. (2006) Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proceedings of the National Academy of Sciences, 103(43), 1621-1626. 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)

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