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Review
, 11 (10), 1934-6

Progressive Endolysosomal Deficits Impair Autophagic Clearance Beginning at Early Asymptomatic Stages in fALS Mice

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Review

Progressive Endolysosomal Deficits Impair Autophagic Clearance Beginning at Early Asymptomatic Stages in fALS Mice

Yuxiang Xie et al. Autophagy.

Abstract

Autophagy is an important homeostatic process that functions by eliminating defective organelles and aggregated proteins over a neuron's lifetime. One pathological hallmark in amyotrophic lateral sclerosis (ALS)-linked motor neurons (MNs) is axonal accumulation of autophagic vacuoles (AVs), thus raising a fundamental question as to whether reduced autophagic clearance due to an impaired lysosomal system contributes to autophagic stress and axonal degeneration. We recently revealed progressive lysosomal deficits in spinal MNs beginning at early asymptomatic stages in fALS-linked mice expressing the human (Hs) SOD1(G93A) protein. Such deficits impair the degradation of AVs engulfing damaged mitochondria from distal axons. These early pathological changes are attributable to mutant HsSOD1, which interferes with dynein-driven endolysosomal trafficking. Elucidation of this pathological mechanism is broadly relevant, because autophagy-lysosomal deficits are associated with several major neurodegenerative diseases. Therefore, enhancing autophagic clearance by rescuing endolysosomal trafficking may be a potential therapeutic strategy for ALS and perhaps other neurodegenerative diseases.

Keywords: ALS; SOD1; autophagy; axonal transport; dynein; late endosome; lysosome; mitochondria; motor neurons; neurodegeneration.

Figures

Figure 1.
Figure 1.
Mutant HsSOD1G93A and SNAPIN play opposite roles in the dynein-driven retrograde transport of late endosomes and lysosome maturation. (A) SNAPIN acts as an adaptor recruiting dynein motors to late endosomes via binding to DNAI, thus coordinating dynein-driven retrograde transport toward the soma and endolysosomal trafficking and lysosomal maturation. This mechanism enables neurons to maintain efficient autophagy-lysosomal degradation capacity. (B) In mutant HsSOD1G93A motor neurons, the SNAPIN-dynein coupling is blocked by HsSODG93A-DNAI interaction, thereby reducing dynein recruitment to late endosomes for driving retrograde transport toward the soma, and impairing lysosome maturation. These phenotypes are readily detectable at early asymptomatic stages of HsSOD1G93A mice. (C) Elevated SNAPIN expression reverses the mutant phenotype by competing with mutant HsSOD1G93A for binding dynein DNAI. By competitively binding to dynein, mutant HsSOD1G93A and SNAPIN play opposite roles in the dynein-driven retrograde transport of late endosomes, and thus autophagy-lysosome function.

Comment on

  • Punctum to: Xie Y, et al. Endolysosome deficits augment mitochondria pathology in spinal motor neurons of asymptomatic fALS-linked mice. Neuron 2015; 87:355-370.

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