Neuromuscular junction dysfunction in a mouse model of Lafora disease.

Lafora disease (LD), a fatal neurodegenerative disorder, is caused by mutations in the EPM2A gene coding laforin phosphatase or NHLRC1 gene coding malin ubiquitin ligase. The LD symptoms include epileptic seizures, ataxia, dementia, and cognitive decline. Studies on LD have primarily concentrated on the pathophysiology in the brain. A few studies have reported motor symptoms, muscle weakness and muscle atrophy. Intriguingly, skeletal muscles are known to accumulate Lafora polyglucosan bodies. Using Laforin-deficient mice, an established model for LD, we demonstrate that LD pathology correlated with structural and functional impairments in the neuromuscular junction (NMJ). Specifically, we find impairment in the NMJ transmission, which coincides with altered expression of NMJ-associated genes and reduced motor endplate area, fragmented junctions and loss of fully innervated junctions at NMJ. We also observe a reduction of alpha motor neurons in the lumbar spinal cord, with significant presynaptic morphological alterations. Disorganized myofibrillar patterns, slight z-line streaming, and muscle atrophy are also evident in LD animals. In summary, our study offers novel insight into the neuropathic and myopathic alterations leading to motor deficits in LD.

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