We will be posting a series of summaries from our 2015 researcher meeting, highlighting some of the most interesting new developments and discoveries presented there. This update covers the special session, “Emerging Trends in Motor Neuron Pathobiology.”
This summary was written by Cure SMA Scientific Advisory Board member Doug Kerr, MD, PhD.
Emerging Trends in Motor Neuron Pathobiology
This session brought in researcher scientists who work in related motor neuron disorders, in order to explore potential connections to SMA.
Individuals with SMA don’t correctly produce survival motor neuron protein (SMN protein) at high enough levels, due to a genetic mutation. Over the preceding several years, we have become increasingly excited about the potential to restore SMN expression from the SMN2 gene.
But there may be other therapies that could also be effective in protecting motor neurons or improving their function. In part, this session emerged from the desire to explore these “non-SMN” based therapies.
We also recognize that our research in SMA and the research in other motor neuron disorders share similar challenges and goals: to know WHAT cells to protect, WHEN we need to protect them, and HOW we can identify new potential therapies.
We started the session with Dr. Don Cleveland from UCSD, one of the leading researchers in amyotrophic lateral sclerosis (ALS). Dr. Cleveland highlighted that SMA shares similarities with ALS, especially in problems with processing RNA, which is the genetic material that leads to protein production in cells. Though SMA and ALS are clearly triggered by distinct things, the motor neuron degeneration in both diseases seems to involve similar problems with how the motor neurons generate, stabilize, and transport RNA molecules. Interestingly, some of the RNA molecules that are most altered in ALS encode for proteins that facilitate synaptic function. “Synaptic function” conducts electrical impulses from neuron to neuron. One intriguing speculation is that motor neuron disorders may involve the alteration of proteins that stabilize these synapses.
Dr. Michael Shy from the University of Iowa is an expert in inherited peripheral nerve diseases. These diseases, which are caused by many different gene mutations, affect the long nerves that come out of the spinal cord and cause weakness and lack of sensation. Dr. Shy noted that, although SMA primarily affects the motor neurons in the spinal cord, it also affects peripheral nerves. Dr. Shy showed that several of the inherited peripheral nerve disorders have gene mutations that impair the function and/or transport of mitochondria in peripheral nerves. Mitochondria are the “powerhouse” of the cell, generating energy for the cell to function. These powerhouses need to function in the peripheral nerves and where the nerve contacts the muscle. This triggered a discussion among the SMA researchers about mitochondrial function and transport of these mitochondria within nerves in SMA.
Kevin Talbot is a physician and scientist from Oxford UK who specializes in both ALS and SMA. Dr. Talbot carried out a series of investigations to determine whether there is a link between SMN deficiency and ALS. He has not yet been able to define a link, but this research is still ongoing. Dr. Talbot then spoke about the importance of protein aggregation in ALS. Protein aggregation occurs when proteins don’t fold into the right structure, forming large deposits within neurons that can be toxic. There may be similar problems in a variety of neurologic diseases, including Alzheimer’s disease and Parkinson’s disease, but it does not seem to be a problem in SMA.
Serge Przedborski is a physician-scientist who has studied the role of diseased non-neuronal cells, such as astrocytes, in the death of neighboring motor neurons in ALS. Although motor neurons become injured in SMA, it is possible that cells nearby those motor neurons contribute to their dysfunction. As we develop therapies for SMA, we should make sure we impact those nearby cells as well as motor neurons. Dr. Przedborski found a new cellular pathway, called necroptosis, that is involved in how astrocytes injure neurons in ALS. And Dr. Przedborski identified several candidate master regulators of this process that may be targets for drug development in ALS. Dr. Przedborski also thinks that this may occur in SMA, meaning these targets may also be relevant to developing therapies for SMA.
Dr. Allison Ebert is a scientist at the Medical College of Wisconsin who has extensively studied the use of stem cells to model diseases like ALS and SMA in a dish. Like Dr. Prezedborski, Dr. Ebert has also looked at the effect that astrocytes and other cells have on motor neurons. Her lab has shown that astrocyte reactivity has been observed in mouse models, human patient spinal cords, and iPSC-derived cultures of SMA. She believes that this reactivity has an impact on both other astrocytes and motor neurons. In addition, replacement of SMN in just astrocytes but not other tissues in the mouse models of SMA does provide benefit. Therefore, Dr. Ebert believes that targeting astrocyte function may be relevant for development of therapies in SMA.
Thank you to Drs. Cleveland, Shy, Talbot, Przedborski, and Ebert for lending their expertise to this session.
Pictured above: Kevin Talbot speaks at the special session.