Lafora disease (LD) is a rare genetic disorder that usually manifests in adults with symptoms of epileptic seizures, involuntary muscle twitching, problems with coordination and cognitive decline. One of the main characteristics is the formation of Lafora bodies, glycogen aggregates caused by malfunction of glycogen metabolism, in tissues like the brain, muscles and liver. As LD is a neurodegenerative condition, most of the current research is focused on its effects on the central nervous system, despite prominent motor symptoms also affecting patients.
Shukla, Chugh and Ganesh used a well-established LD mouse model but, instead of focusing on the central nervous system, they investigated the underlying mechanism of previously observed motor symptoms in mice aged 5 and 10 months. Specifically, the authors focused on the changes in neuromuscular junctions (NMJs).
The authors used electrophysiological recording techniques to investigate the response of the hindlimb gastrocnemius muscle after sciatic nerve stimulation. They discovered that repetitive nerve stimulation led to a gradual decrease in muscle electrical activity in LD mice, whereas activity stayed the same in control mice. When using immunofluorescence staining and transmission electron microscopy to visualise NMJs, they observed a decrease in complexity of these structures compared to that of the control. Furthermore, the authors discovered that the muscle site of the NMJ was less innervated in the LD mouse model, and that this was more prominent in 10-month-old compared with 5-month-old mice. In an attempt to compensate for the lack of innervation, NMJ neurons started to sprout, which was also more pronounced in older mice. Further staining showed loss and atypical morphological changes of motor neurons, as well as accumulation of Lafora bodies and activated non-healthy glial cells, which usually function to surround and protect the motor neurons in the spinal cord. Muscles were also affected, showing progressive decrease in mass and an increase in response delay time.
Overall, this study links pathological glycogen accumulation, glial cell activation and motor neuron degeneration in the LD mouse model, and confirms that LD affects not only the central nervous system but also peripheral neurons, muscles and NMJs. Research on the mechanisms underlying LD symptoms in mouse models paves the way to understanding the progression of this disease in humans and may help identify possible strategies for future treatments.
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