Using Biophysics to Uncover the Mechanisms of Neuromuscular Degeneration in ALS

The Biophysical Society is an an international society, with over 35% of its members residing outside the United States.  Thus, for this month’s feature on the relationship between biophysics research and disease, we are looking at ALS in honor of ALS Awareness Month in Canada.  Society member Jingsong Zhou, an Associate Professor in the Department of Molecular Biophysics and Physiology at Rush University Medical Center, is working hard in her lab to develop a deep understanding of the disease mechanism in hopes of that understanding contributing to new therapeutics and a better prognosis for those with ALS.

These are images of single muscle cells (“fibers”) derived from an ALS mouse model (G93A). The A panels show absence of electrically well-polarized mitochondria (marked by mitochondrial membrane potential probes, TMRE in green) in the vicinity of the neuromuscular junction (identified by alpha-BTX in red). The B panels show simultaneous imaging of mitochondrial function (marked by TMRE in red) and calcium release activity (indicated by a calcium dye, fluo-4 in blue) of G93A muscle fibers. Lack of TMRE staining identifies fiber segments with defective mitochondria (1). Note that calcium release activity is greater in the segments with defective mitochondria (2). (Zhou et al., JBC, 2010).

What is the connection between your research and ALS?
The goal of my laboratory is to explore the molecular mechanism underlying neuromuscular degeneration during ALS progression. Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease characterized by progressive motor neuron death and skeletal muscle atrophy and paralysis. Most patients die within 5 years of the disease onset. The lifetime risk of ALS is about 1 in 500. Since ALS is an age-dependent disease, as the U.S. population increases and ages, an increase in the prevalence of ALS can be anticipated. Despite intensive research efforts, there is no effective cure for ALS. My laboratory hopes to identify potential therapeutic means to alleviate ALS progression.

Why is your research important to those concerned about these diseases?
During ALS progression, the degeneration of motor neuron limits neuron-to-muscle signaling and leads to severe muscle atrophy, while the retrograde signaling from muscle-to-neuron, which is important for axonal growth and neuromuscular junction maintenance, is also lost in ALS progression. There are research groups that focus on muscle physiology, while others focus on understanding the mechanism of motor neuron degeneration. Taking advantage of working closely with both muscle and neuron groups, we are conducting translational research that bridges studies on the pathophysiology of muscle and motor neurons in ALS. My lab has been developing various genetic mouse models and molecular probes to examine the functional interplay between the neuron and muscle and between the intracellular organelles during the progression of muscle wasting in ALS. The signals reported by those molecular probes represent functional indices of ALS progression. In addition to understand the molecular mechanisms underlying the degeneration of motor neurons and skeletal muscle, our genetic model systems allow us to evaluate whether potential interventions have a beneficial effect on ALS.

How did you get into this area of research?
After graduating from Xiangya Medical College, I found my passion in medical research. Luckily I was accepted by Dr. Eduardo Rios as his first Ph.D. student at Rush University and trained as a muscle physiologist with a focus on understanding how calcium signaling is controlled during muscle contraction. As a core muscle physiologist I have been often asked how I found my career path in ALS research. The collaboration with Dr. Rios led us to examine the role of mitochondria in regulating fast calcium signaling during muscle contraction. My medical training also puts my interests in studying diseases. I wondered the role of mitochondria in regulation of calcium signaling in muscle pathophysiology. Dr. Han-Xiang Deng at Northwestern University is among the scientists who first identified ALS mutations and generated ALS mouse models. We graduated from the same medical school and often had interesting scientific discussions, which inspired me to begin my research in ALS. The mitochondrial defect is a pathologic hallmark in motor neurons during ALS progression. Skeletal muscle comprises around 40% of whole-body lean mass and is substantially affected in ALS. But little is known about the role of mitochondria in muscle degeneration during ALS progression. Using an ALS mouse model provided by Dr. Deng, I initiated my research in ALS by examining mitochondrial function and calcium signaling in skeletal muscle of ALS.

How long have you been working on it?
In 2006, we obtained the first ALS mouse from Dr. Deng. Since then, our efforts never end to understand the mechanisms of neuromuscular degeneration in ALS and to explore potential therapeutic interventions to treat ALS.

What organizations funded your work?
In the past 8 years, my research in ALS was first funded by the Muscular Dystrophy Association USA (MDA) and continuously funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at NIH.

Have you had any surprise findings thus far?
Most ALS cases are sporadic (SALS), with about 10% being familial (FALS). Both SALS and FALS manifest similar pathological and clinical phenotypes, suggesting that different initiating causes lead to a mechanistically similar neurodegenerative pathway. Mouse models expressing ALS-linked mutations effectively recapitulate many features of the human disease. By studying live skeletal muscle of an ALS mouse model, we have discovered that there are localized mitochondrial defects, which occur near the site of the neuromuscular junction and lead to uncontrolled intracellular calcium transients. This finding opens a new window to understand the role of mitochondria and calcium signaling in the crosstalk between muscle and neuron during ALS progression and to target the neuromuscular junction for developing potential therapeutic means to combat ALS. In addition, mitochondria are dynamic organelles that constantly undergo fusion and fission to maintain their normal functionality. We have found that ALS mutations directly slow down the dynamics of mitochondria in ALS skeletal muscle, suggesting skeletal muscle is also a primary target of ALS mutation. Restoring mitochondrial function in skeletal muscle could provide potentially beneficial effects for alleviating muscle wasting and slowing down disease progression.

What is particularly interesting about the work from the perspective of other researchers?
Our research defines the role of Ca2+ signaling and mitochondrial function in health and diseased skeletal muscle. I am particularly interested in the control of local intracellular Ca2+ signals mediated by the interaction between the SR (sarcoplasmic reticulum) and mitochondria. The mechanisms controlling this signaling represent critical points at which many cellular phenomena (e.g. contraction, secretion, transcription, etc) can be modulated. This work is thus clinically important because it defines potential sites for pathological failure and/or therapeutic intervention in many other diseases.

What is particularly interesting about the work from the perspective of the public?
ALS is an age-dependent fatal disease with no cure. The only FDA-approved treatment for ALS, Riluzole, only extends patients’ life for a few months and has limited efficacy on symptom relief. New treatments are needed for improving the life quality of ALS patients. Relying on deep understanding of the disease mechanism, our research may lead to advances in developing therapeutic interventions.








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