title: Mice deficient in Epg5 exhibit selective neuronal vulnerability to degeneration.
abstract: The molecular mechanism underlying the selective vulnerability of certain neuronal populations associated with neurodegenerative diseases remains poorly understood. Basal autophagy is important for maintaining axonal homeostasis and preventing neurodegeneration. In this paper, we demonstrate that mice deficient in the metazoan-specific autophagy gene Epg5/epg-5 exhibit selective damage of cortical layer 5 pyramidal neurons and spinal cord motor neurons. Pathologically, Epg5 knockout mice suffered muscle denervation, myofiber atrophy, late-onset progressive hindquarter paralysis, and dramatically reduced survival, recapitulating key features of amyotrophic lateral sclerosis (ALS). Epg5 deficiency impaired autophagic flux by blocking the maturation of autophagosomes into degradative autolysosomes, leading to accumulation of p62 aggregates and ubiquitin-positive inclusions in neurons and glial cells. Epg5 knockdown also impaired endocytic trafficking. Our study establishes Epg5-deficient mice as a model for investigating the pathogenesis of ALS and indicates that dysfunction of the autophagic-endolysosomal system causes selective damage of neurons associated with neurodegenerative diseases.
authors.affiliation: College of Life Sciences, China Agricultural University, Beijing 100083, China.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.forename: Yan G
authors.initials: YG
authors.lastname: Zhao
authors.forename: Xingwei
authors.initials: X
authors.lastname: Wang
authors.forename: Lanjun
authors.initials: L
authors.lastname: Xu
authors.forename: Lin
authors.initials: L
authors.lastname: Miao
authors.forename: Du
authors.initials: D
authors.lastname: Feng
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
authors.forename: Attila L
authors.initials: AL
authors.lastname: Kovács
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Fan
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001343:Autophagy; D000071183:Autophagy-Related Proteins; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D010243:Paralysis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010588:Phagosomes / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism* / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D033921:Vesicular Transport Proteins
chemical_list: D000071183:Autophagy-Related Proteins; C581266:Epg5 protein, mouse; D011506:Proteins; D033921:Vesicular Transport Proteins