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Wide-ranging Neuromuscular Effects of C9orf72 Loss in ALS
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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with C9orf72 repeat expansions and SOD1 mutations representing the most common genetic causes. Beyond toxic gain-of-function (GOF) species, C9orf72 loss-of-function (LOF) is increasingly recognized as a contributor to ALS pathology, particularly through effects on glial and immune regulation. In addition, the impact of C9orf72 disruption on peripheral nervous system (PNS) function is receiving greater scrutiny.
A new study in Journal of Neuroinflammation provides clear evidence that C9orf72 LOF disrupts peripheral neuromuscular stability (1). Using C9orf72 knockout and SOD1G93A mouse models, the authors show that C9orf72 is essential for Schwann cell function, peripheral myelination, and neuromuscular junction (NMJ) integrity. C9orf72-deficient mice exhibited hypomyelination, radial sorting defects, polyaxonal myelination, and partial NMJ denervation, along with strong peripheral immune activation. In SOD1G93A/C9orf72 double-mutant mice, C9orf72 LOF accelerated ALS onset and intensified axonal and mitochondrial pathology without additional motor neuron loss. The results highlight peripheral glial dysfunction and immune imbalance as key drivers of ALS progression and support therapeutic approaches that restore C9orf72 function.
The C9orf72 antibody [GT1553] (GTX634482) was utilized for western blot and immunohistochemistry in this study, enabling clear detection of C9orf72 in motor neurons, Schwann cells, oligodendrocytes, and microglia. Antibody specificity was established by comparing tissue images from wild-type and C9orf72-knockout mice.
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