Mice deficient in epg5 exhibit selective neuronal vulnerability to degeneration

Hongyu Zhao, Yan G. Zhao, Xingwei Wang, Lanjun Xu, Lin Miao, Du Feng, Quan Chen, A. Kovács, Dongsheng Fan, Hong Zhang

Research output: Contribution to journalArticle

64 Citations (Scopus)

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 inndi- cates that dysfunction of the autophagic-endolysosomal system causes selective damage of neurons associated with neurodegenerative diseases.

Original languageEnglish
Pages (from-to)731-741
Number of pages11
JournalJournal of Cell Biology
Volume200
Issue number6
DOIs
Publication statusPublished - Mar 2013

Fingerprint

Autophagy
Amyotrophic Lateral Sclerosis
Neurodegenerative Diseases
Muscle Denervation
Neurons
Pyramidal Cells
Motor Neurons
Ubiquitin
Knockout Mice
Neuroglia
Paralysis
Atrophy
Spinal Cord
Homeostasis
Population
Genes
Autophagosomes

ASJC Scopus subject areas

  • Cell Biology
  • Medicine(all)

Cite this

Zhao, H., Zhao, Y. G., Wang, X., Xu, L., Miao, L., Feng, D., ... Zhang, H. (2013). Mice deficient in epg5 exhibit selective neuronal vulnerability to degeneration. Journal of Cell Biology, 200(6), 731-741. https://doi.org/10.1083/jcb.201211014

Mice deficient in epg5 exhibit selective neuronal vulnerability to degeneration. / Zhao, Hongyu; Zhao, Yan G.; Wang, Xingwei; Xu, Lanjun; Miao, Lin; Feng, Du; Chen, Quan; Kovács, A.; Fan, Dongsheng; Zhang, Hong.

In: Journal of Cell Biology, Vol. 200, No. 6, 03.2013, p. 731-741.

Research output: Contribution to journalArticle

Zhao, H, Zhao, YG, Wang, X, Xu, L, Miao, L, Feng, D, Chen, Q, Kovács, A, Fan, D & Zhang, H 2013, 'Mice deficient in epg5 exhibit selective neuronal vulnerability to degeneration', Journal of Cell Biology, vol. 200, no. 6, pp. 731-741. https://doi.org/10.1083/jcb.201211014
Zhao, Hongyu ; Zhao, Yan G. ; Wang, Xingwei ; Xu, Lanjun ; Miao, Lin ; Feng, Du ; Chen, Quan ; Kovács, A. ; Fan, Dongsheng ; Zhang, Hong. / Mice deficient in epg5 exhibit selective neuronal vulnerability to degeneration. In: Journal of Cell Biology. 2013 ; Vol. 200, No. 6. pp. 731-741.
@article{844b7c872f8742429588827d61088d50,
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 inndi- cates that dysfunction of the autophagic-endolysosomal system causes selective damage of neurons associated with neurodegenerative diseases.",
author = "Hongyu Zhao and Zhao, {Yan G.} and Xingwei Wang and Lanjun Xu and Lin Miao and Du Feng and Quan Chen and A. Kov{\'a}cs and Dongsheng Fan and Hong Zhang",
year = "2013",
month = "3",
doi = "10.1083/jcb.201211014",
language = "English",
volume = "200",
pages = "731--741",
journal = "Journal of Cell Biology",
issn = "0021-9525",
publisher = "Rockefeller University Press",
number = "6",

}

TY - JOUR

T1 - Mice deficient in epg5 exhibit selective neuronal vulnerability to degeneration

AU - Zhao, Hongyu

AU - Zhao, Yan G.

AU - Wang, Xingwei

AU - Xu, Lanjun

AU - Miao, Lin

AU - Feng, Du

AU - Chen, Quan

AU - Kovács, A.

AU - Fan, Dongsheng

AU - Zhang, Hong

PY - 2013/3

Y1 - 2013/3

N2 - 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 inndi- cates that dysfunction of the autophagic-endolysosomal system causes selective damage of neurons associated with neurodegenerative diseases.

AB - 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 inndi- cates that dysfunction of the autophagic-endolysosomal system causes selective damage of neurons associated with neurodegenerative diseases.

UR - http://www.scopus.com/inward/record.url?scp=84876308090&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876308090&partnerID=8YFLogxK

U2 - 10.1083/jcb.201211014

DO - 10.1083/jcb.201211014

M3 - Article

C2 - 23479740

AN - SCOPUS:84876308090

VL - 200

SP - 731

EP - 741

JO - Journal of Cell Biology

JF - Journal of Cell Biology

SN - 0021-9525

IS - 6

ER -