Mitochondrial dysfunction and neuromuscular junction (NMJ) decline are both prominent features in amyotrophic lateral sclerosis (ALS), and implicated in the onset and progression of ALS. However, whether and how mitochondrial dysfunction plays a role in NMJ decline in ALS is not clear. Constant mitochondrial fission and fusion dynamics are essential for both mitochondrial morphology and function. We and others recently demonstrated that the impaired mitochondrial fission and fusion dynamics was likely an important mechanism leading to mitochondrial dysfunction and neurodegeneration in ALS and other various major neurodegenerative diseases. Interestingly, in our preliminary studies, we found that mitochondria became highly fragmented in spinal cord motor neurons of ALS patients and the widely studied transgenic SOD1 G93A mouse model of ALS (SOD1G93A mice). Mitofusin 2 (Mfn2), the key regulator of mitochondrial fusion, was further found to be reduced in spinal cords of ALS patients and SOD1G93A mice. Excitingly, our newly identified Mfn2 degradation pathway via calpain was found activated in SOD1G93A mice. Mfn2 deficiency in motor neurons caused mitochondrial fragmentation, NMJ denervation and neuronal death, whereas forced expression of Mfn2 in neurons was sufficient to completely abolish mitochondrial fragmentation, NMJ decline and related skeletal muscle atrophy in SOD1G93A mice even at the endstage. These exciting and promising preliminary studies suggest that a detailed investigation into the potential role of Mfn2 in the maintenance of NMJs and related skeletal muscles in ALS is warranted. The following specific aims will be pursued: 1) To perform detailed assessments of motor function, skeletal muscles, motor neurons and NMJs in Mfn2/SOD1G93A mice; 2) To elucidate the molecular mechanism underlying Mfn2 reduction in SOD1G93A mice and validate calpain-mediated Mfn2 degradation as a therapeutic target; 3) To explore the pathways by which neuronal Mfn2 protects NMJs in Mfn2/SOD1G93A mice. This will be first systematic and mechanistic in vivo study using novel mouse models, a promising novel synthetic therapeutic peptide and cross-disciplinary approaches to investigate the role of mitochondrial dynamics in the maintenance of NMJs and function of motor neuron and muscle in ALS. Our proposed studies of the impact of mitochondrial dynamics on NMJs as a functional unit of nerve and muscle in the context of ALS will has both scientific (new insight into mechanisms underlying mitochondrial dysfunction and NMJ decline in ALS) and translational (provide novel therapeutic approaches to delay or reverse NMJ decline and associated skeletal muscle atrophy in ALS) significance.

Public Health Relevance

Neuromuscular junction (NMJ) decline plays an important role in muscle atrophies in amyotrophic lateral sclerosis (ALS). Although mitochondrial dysfunction is one of the most prominent feature in ALS, whether and how mitochondria contribute to ALS-related dysfunction of NMJ and muscles is still not clear. Mitochondria are highly dynamic organelles that undergo continual fission/fusion events which are critical for the maintenance of mitochondrial function. Previous studies from our and other groups have consistently showed mitochondrial fission/fusion dynamic abnormalities in ALS experimental models. Here, we propose to investigate whether mitochondrial dynamics are involved in the progression of mitochondrial dysfunction, NMJ decline and nerve and muscle dysfunction in ALS transgenic mice in vivo, and more importantly, test whether the manipulation of mitochondrial dynamics could slow or reverse NMJ decline and muscle atrophies in ALS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Gubitz, Amelie
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Case Western Reserve University
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Wang, Luwen; Gao, Ju; Liu, Jingyi et al. (2018) Mitofusin 2 Regulates Axonal Transport of Calpastatin to Prevent Neuromuscular Synaptic Elimination in Skeletal Muscles. Cell Metab 28:400-414.e8
Gao, Ju; Wang, Luwen; Liu, Jingyi et al. (2017) Abnormalities of Mitochondrial Dynamics in Neurodegenerative Diseases. Antioxidants (Basel) 6: