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Updated: Apr 7, 2026
Expanding the Toolkit for In Vivo Imaging of Axonal Transport
Published on: December 23, 2021
Endolysosomal Deficits Augment Mitochondria Pathology in Spinal Motor Neurons of Asymptomatic fALS Mice
Yuxiang Xie1, Bing Zhou1, Mei-Yao Lin1
1Synaptic Functions Section, The Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Room 2B-215, 35 Convent Drive, Bethesda, MD 20892-3706, USA.
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 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.
Insights
In familial ALS, motor neurons show impaired mitochondria removal due to lysosomal deficits, even before symptoms appear. Restoring transport mechanisms rescues motor neuron function and improves survival in mouse models.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Motor neuron degeneration in Amyotrophic Lateral Sclerosis (ALS) is linked to axonal mitochondrial accumulation.
- The role of impaired autophagy-lysosomal pathways in this mitochondrial pathology remains unclear.
Purpose of the Study:
- To investigate the contribution of autophagy-lysosomal deficits to mitochondrial pathology in motor neurons of ALS models.
- To explore the therapeutic potential of targeting transport mechanisms.
Main Methods:
- Utilized hSOD1(G93A) mouse models of familial ALS (fALS).
- Performed live imaging of spinal motor neurons to assess organelle transport.
- Investigated the impact of expressing snapin on dynein-mediated transport and lysosomal function.
Main Results:
- Identified progressive lysosomal deficits and impaired autophagic degradation in motor neurons at asymptomatic stages.
- Observed accumulation of autophagic vacuoles containing damaged mitochondria.
- Demonstrated that expressing snapin rescues retrograde transport defects, enhances mitochondrial turnover, improves motor neuron survival, and ameliorates disease phenotype.
Conclusions:
- Established a mechanistic link between hSOD1(G93A) expression, impaired late endosome transport, and autophagy-lysosomal deficits.
- Mitochondrial pathology in ALS motor neurons is exacerbated by reduced degradation of damaged mitochondria.
- Targeting dynein-mediated transport offers a potential therapeutic strategy for fALS.
