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

Friday, September 18, 2015 — Poster Session V

2:00 p.m. – 3:30 p.m.
FAES Terrace
NINDS
NEURO-51

Authors

  • Y Xie
  • B Zhou
  • M Lin
  • S Wang
  • K Foust
  • Z Sheng

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 impaired autophagy-lysosomal system contribute to mitochondrial pathology? Here, we reveal MN-targeted progressive lysosomal deficits accompanied by impaired autophagic degradation beginning at asymptomatic stages in fALS-linked hSOD1G93A 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 hSOD1G93A for binding dynein, thus rescuing autophagy-lysosomal deficits, enhancing mitochondria turnover, improving MN survival, and ameliorating the disease phenotype in hSOD1G93A mice. Our study provides a new mechanistic link for hSOD1G93A-mediated impairment of LE transport to autophagy-lysosome deficits and mitochondria pathology. Understanding these early pathological events benefits development of new therapeutic interventions for fALS-linked MN degeneration.

Category: Neuroscience