Disruption of the PAR3/INSC/LGN complex causes microtubule instability and peripheral neuropathy

Abstract

AbstractPAR3/INSC/LGN form an evolutionarily conserved complex required for asymmetric cell division in the developing brain, but its post-developmental function and disease relevance in the peripheral nervous system (PNS) remains unknown. We mapped a new locus for axonal Charcot-Marie-Tooth disease (CMT2) and identified a missense mutation c.209T>G (p.Met70Arg) in the INSC (INSC) gene. Modelling theINSCM70Rvariant inDrosophila, we showed that it caused proprioceptive defects in adult flies, leading to gait defects resembling those in CMT2 patients. Cellularly, PAR3/INSC/LGN dysfunction caused tubulin aggregation and necrotic neurodegeneration, with microtubule-stabilizing agents rescuing both morphological and functional defects of theINSCM70Rmutation in the PNS. Our findings underscore the critical role of the PAR3/INSC/LGN machinery in the adult PNS and highlights a potential therapeutic target for INSC-associated CMT2.One-Sentence SummaryPAR3/INSC/LGN dysfunction causes peripheral neuropathy and is potentially treatable by stabilizing the microtubule network.