부산대학교 도서관

Hexanucleotide repeat expansions in the C9orf72 gene is the prevalent genetic cause of ALS, causing neurodegeneration through two gain-of-function mechanisms due to the accumulation of RNA foci and dipeptide-repeat proteins, and a loss-of-function mechanism due to C9orf72 protein reduction. The loss-of-function has never been examined in the peripheral compartment of neuromuscular system, precociously affected by ALS. In this work we observed that C9orf72 is expressed by Schwann cells and skeletal muscle in mice and the constitutive ablation of C9orf72 leads to mild muscle denervation, alterations of autophagy, increased immune cell infiltration and inflammation in muscle and peripheral nerve, typical features of ALS. Moreover, demyelination, activation of Schwann cells in a repair mode and autoimmunity were found in peripheral nerves of C9orf72-/- mice. Evidence demonstrates that the loss-of-function synergizes with other toxic stimuli to induce neurodegeneration. Moreover, C9orf72 mutation often occurs in combination with other ALS or FTD-linked genes, suggesting oligogenicity of ALS. Therefore, to verify whether the C9orf72 loss-of-function could act as ALS modulator, we investigated the effect of C9orf72 constitutive ablation in SOD1G93A mice, the best characterized model of ALS. We found that the C9orf72 loss-of-function anticipated the onset of symptoms exacerbating denervation, autophagy impairment and inflammation in muscle, and enhancing axonal transport disruption in SOD1G93A mice. Conversely, increased anti-inflammatory gliosis in the spinal cord and extended survival were detected in SOD1G93A C9orf72-/- mice. For the first time, in this work we demonstrated that C9orf72 is expressed in the peripheral compartment of neuromuscular system where it is pivotal in maintaining the homeostasis. Despite the C9orf72 ablation had detrimental effects on this district and anticipated the symptom onset in ALS mice, unexpectedly it prolonged their lifespan. This suggests that reducing the C9orf72 expression in the later phase of the disease, for example through antisense oligonucleotides, might have a therapeutic relevance.