Endolysosomal Deficits Augment Mitochondria Pathology in Spinal Motor Neurons of Asymptomatic fALS Mice.

ABSTRACT: 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

SUBMITTER: Xie Y 

PROVIDER: S-EPMC4511489 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature