title: 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 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.
authors.affiliation: Synaptic 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.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Synaptic 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.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Synaptic 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.
authors.forename: Mei-Yao
authors.initials: MY
authors.lastname: Lin
authors.affiliation: Synaptic 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.
authors.forename: Shiwei
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Neuroscience, Ohio State University, 698 BRT, 460 West 12th Avenue, Columbus, OH 43210, USA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Foust
authors.affiliation: Synaptic 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. Electronic address: shengz@ninds.nih.gov.
authors.forename: Zu-Hang
authors.initials: ZH
authors.lastname: Sheng
mesh_terms: D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008247:Lysosomes / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics; D013997:Time Factors; D014161:Transduction, Genetic; D044767:Ubiquitin-Protein Ligases; D033921:Vesicular Transport Proteins / Q000627:therapeutic use; D000070584:Tripartite Motif Proteins
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D013482:Superoxide Dismutase; D044767:Ubiquitin-Protein Ligases; D033921:Vesicular Transport Proteins; C498451:Snapin protein, mouse; C109415:SOD1 G93A protein; C489296:Trim27 protein, mouse; D000070584:Tripartite Motif Proteins