Mice deficient in <i>Epg5</i> exhibit selective neuronal vulnerability to degeneration

DOI PDF 被引用文献7件
  • Hongyu Zhao
    College of Life Sciences, China Agricultural University, Beijing 100083, China 1
  • Yan G. Zhao
    State Key Laboratory of Biomacromolecules, Institute of Biophysics 2 ; and 3
  • Xingwei Wang
    State Key Laboratory of Biomacromolecules, Institute of Biophysics 2 ; and 3
  • Lanjun Xu
    State Key Laboratory of Biomacromolecules, Institute of Biophysics 2 ; and 3
  • Lin Miao
    National Institute of Biological Sciences, Beijing 102206, China 4
  • Du Feng
    Institute of Neurology, Affiliated Hospital of Guangdong Medical College, Zhanjiang 524001, China 5
  • Quan Chen
    State Key Laboratory of Biomacromolecules, Institute of Biophysics 2 ; and 3
  • Attila L. Kovács
    Department of Anatomy, Cell, and Developmental Biology, Eötvös Loránd University, Budapest H-1117, Hungary 6
  • Dongsheng Fan
    Department of Neurology, Peking University Third Hospital, Beijing 100191, China 7
  • Hong Zhang
    State Key Laboratory of Biomacromolecules, Institute of Biophysics 2 ; and 3

説明

<jats:p>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.</jats:p>

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