One pathological hallmark in ALS motor neurons (MNs) is axonal accumulation of damaged mitochondria. A fundamental question remains: does reduced degradation of those mitochondria by an impaired autophagy-lysosomal system contribute to mitochondrial pathology? We reveal MN-targeted progressive lysosomal deficits accompanied by impaired autophagic degradation beginning at asymptomatic stages in fALS-linked hSOD1(G93A) mice. Lysosomal deficits result in accumulation of autophagic vacuoles engulfing damaged mitochondria along MN axons. Live imaging of spinal MNs from the adult disease mice demonstrates impaired dynein-driven retrograde transport of late endosomes (LEs). Expressing dynein-adaptor snapin reverses transport defects by competing with hSOD1(G93A) for binding dynein, thus rescuing autophagy-lysosomal deficits, enhancing mitochondrial turnover, improving MN survival, and ameliorating the disease phenotype in hSOD1(G93A) mice. Our study provides a new mechanistic link for hSOD1(G93A)-mediated impairment of LE transport to autophagy-lysosomal deficits and mitochondrial pathology. Understanding these early pathological events benefits development of new therapeutic interventions for fALS-linked MN degeneration.
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