Progressive endolysosomal deficits impair autophagic clearance beginning at early asymptomatic stages in fALS mice.
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.
a Synaptic Functions Section; The Porter Neuroscience Research Center; National Institute of Neurological Disorders and Stroke; National Institutes of Health ; Bethesda , MD USA.
Yuxiang
Y
Xie
a Synaptic Functions Section; The Porter Neuroscience Research Center; National Institute of Neurological Disorders and Stroke; National Institutes of Health ; Bethesda , MD USA.
Bing
B
Zhou
a Synaptic Functions Section; The Porter Neuroscience Research Center; National Institute of Neurological Disorders and Stroke; National Institutes of Health ; Bethesda , MD USA.
Mei-Yao
MY
Lin
a Synaptic Functions Section; The Porter Neuroscience Research Center; National Institute of Neurological Disorders and Stroke; National Institutes of Health ; Bethesda , MD USA.
Zu-Hang
ZH
Sheng
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D004195:Disease Models, Animal; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D009046:Motor Neurons / Q000473:pathology*; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology
ALS; SOD1; autophagy; axonal transport; dynein; late endosome; lysosome; mitochondria; motor neurons; neurodegeneration