Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway

Keiichi Inoue, Joanne Rispoli, Hanoch Kaphzan, Eric Klann, Emily I. Chen, Jongpil Kim, Masaaki Komatsu, Asa Abeliovich

Research output: Contribution to journalArticle

Abstract

Background: Macroautophagy is an evolutionarily conserved mechanism for bulk intracellular degradation of proteins and organelles. Pathological studies have implicated macroautophagy defects in human neurodegenerative disorders of aging including Alzheimer's disease and tauopathies. Neuronal deficiency of macroautophagy throughout mouse embryonic development results in neurodevelopmental defects and early postnatal mortality. However, the role of macroautophagy in mature CNS neurons, and the relationship with human disease neuropathology, remains unclear. Here we describe mice deficient in an essential macroautophagy component, Atg7, specifically within postnatal CNS neurons. Results: Postnatal forebrain-specific Atg7 conditional knockout (cKO) mice displayed age-dependent neurodegeneration and ubiquitin- and p62-positive inclusions. Phosphorylated tau was significantly accumulated in Atg7 cKO brains, but neurofibrillary tangles that typify end-stage human tauopathy were not apparent. A major tau kinase, glycogen synthase kinase 3β (GSK3β), was also accumulated in Atg7 cKO brains. Chronic pharmacological inhibition of tau phosphorylation, or genetic deletion of tau, significantly rescued Atg7-deficiency-mediated neurodegeneration, but did not suppress inclusion formation. Conclusions: These data elucidate a role for macroautophagy in the long-term survival and physiological function of adult CNS neurons. Neurodegeneration in the context of macroautophagy deficiency is mediated through a phospho-tau pathway.

Original languageEnglish (US)
Article number48
JournalMolecular Neurodegeneration
Volume7
Issue number1
DOIs
StatePublished - 2012

Fingerprint

Autophagy
Tauopathies
Neurons
Glycogen Synthase Kinase 3
Neurofibrillary Tangles
Brain
Prosencephalon
Ubiquitin
Knockout Mice
Neurodegenerative Diseases
Organelles
Proteolysis
Embryonic Development
Alzheimer Disease
Phosphotransferases
Phosphorylation
Pharmacology
Survival
Mortality

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Cite this

Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway. / Inoue, Keiichi; Rispoli, Joanne; Kaphzan, Hanoch; Klann, Eric; Chen, Emily I.; Kim, Jongpil; Komatsu, Masaaki; Abeliovich, Asa.

In: Molecular Neurodegeneration, Vol. 7, No. 1, 48, 2012.

Research output: Contribution to journalArticle

Inoue, Keiichi ; Rispoli, Joanne ; Kaphzan, Hanoch ; Klann, Eric ; Chen, Emily I. ; Kim, Jongpil ; Komatsu, Masaaki ; Abeliovich, Asa. / Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway. In: Molecular Neurodegeneration. 2012 ; Vol. 7, No. 1.
@article{8dc560bad3d34e19ba1cdaedbdd1b28d,
title = "Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway",
abstract = "Background: Macroautophagy is an evolutionarily conserved mechanism for bulk intracellular degradation of proteins and organelles. Pathological studies have implicated macroautophagy defects in human neurodegenerative disorders of aging including Alzheimer's disease and tauopathies. Neuronal deficiency of macroautophagy throughout mouse embryonic development results in neurodevelopmental defects and early postnatal mortality. However, the role of macroautophagy in mature CNS neurons, and the relationship with human disease neuropathology, remains unclear. Here we describe mice deficient in an essential macroautophagy component, Atg7, specifically within postnatal CNS neurons. Results: Postnatal forebrain-specific Atg7 conditional knockout (cKO) mice displayed age-dependent neurodegeneration and ubiquitin- and p62-positive inclusions. Phosphorylated tau was significantly accumulated in Atg7 cKO brains, but neurofibrillary tangles that typify end-stage human tauopathy were not apparent. A major tau kinase, glycogen synthase kinase 3β (GSK3β), was also accumulated in Atg7 cKO brains. Chronic pharmacological inhibition of tau phosphorylation, or genetic deletion of tau, significantly rescued Atg7-deficiency-mediated neurodegeneration, but did not suppress inclusion formation. Conclusions: These data elucidate a role for macroautophagy in the long-term survival and physiological function of adult CNS neurons. Neurodegeneration in the context of macroautophagy deficiency is mediated through a phospho-tau pathway.",
author = "Keiichi Inoue and Joanne Rispoli and Hanoch Kaphzan and Eric Klann and Chen, {Emily I.} and Jongpil Kim and Masaaki Komatsu and Asa Abeliovich",
year = "2012",
doi = "10.1186/1750-1326-7-48",
language = "English (US)",
volume = "7",
journal = "Molecular Neurodegeneration",
issn = "1750-1326",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway

AU - Inoue, Keiichi

AU - Rispoli, Joanne

AU - Kaphzan, Hanoch

AU - Klann, Eric

AU - Chen, Emily I.

AU - Kim, Jongpil

AU - Komatsu, Masaaki

AU - Abeliovich, Asa

PY - 2012

Y1 - 2012

N2 - Background: Macroautophagy is an evolutionarily conserved mechanism for bulk intracellular degradation of proteins and organelles. Pathological studies have implicated macroautophagy defects in human neurodegenerative disorders of aging including Alzheimer's disease and tauopathies. Neuronal deficiency of macroautophagy throughout mouse embryonic development results in neurodevelopmental defects and early postnatal mortality. However, the role of macroautophagy in mature CNS neurons, and the relationship with human disease neuropathology, remains unclear. Here we describe mice deficient in an essential macroautophagy component, Atg7, specifically within postnatal CNS neurons. Results: Postnatal forebrain-specific Atg7 conditional knockout (cKO) mice displayed age-dependent neurodegeneration and ubiquitin- and p62-positive inclusions. Phosphorylated tau was significantly accumulated in Atg7 cKO brains, but neurofibrillary tangles that typify end-stage human tauopathy were not apparent. A major tau kinase, glycogen synthase kinase 3β (GSK3β), was also accumulated in Atg7 cKO brains. Chronic pharmacological inhibition of tau phosphorylation, or genetic deletion of tau, significantly rescued Atg7-deficiency-mediated neurodegeneration, but did not suppress inclusion formation. Conclusions: These data elucidate a role for macroautophagy in the long-term survival and physiological function of adult CNS neurons. Neurodegeneration in the context of macroautophagy deficiency is mediated through a phospho-tau pathway.

AB - Background: Macroautophagy is an evolutionarily conserved mechanism for bulk intracellular degradation of proteins and organelles. Pathological studies have implicated macroautophagy defects in human neurodegenerative disorders of aging including Alzheimer's disease and tauopathies. Neuronal deficiency of macroautophagy throughout mouse embryonic development results in neurodevelopmental defects and early postnatal mortality. However, the role of macroautophagy in mature CNS neurons, and the relationship with human disease neuropathology, remains unclear. Here we describe mice deficient in an essential macroautophagy component, Atg7, specifically within postnatal CNS neurons. Results: Postnatal forebrain-specific Atg7 conditional knockout (cKO) mice displayed age-dependent neurodegeneration and ubiquitin- and p62-positive inclusions. Phosphorylated tau was significantly accumulated in Atg7 cKO brains, but neurofibrillary tangles that typify end-stage human tauopathy were not apparent. A major tau kinase, glycogen synthase kinase 3β (GSK3β), was also accumulated in Atg7 cKO brains. Chronic pharmacological inhibition of tau phosphorylation, or genetic deletion of tau, significantly rescued Atg7-deficiency-mediated neurodegeneration, but did not suppress inclusion formation. Conclusions: These data elucidate a role for macroautophagy in the long-term survival and physiological function of adult CNS neurons. Neurodegeneration in the context of macroautophagy deficiency is mediated through a phospho-tau pathway.

UR - http://www.scopus.com/inward/record.url?scp=84866519178&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866519178&partnerID=8YFLogxK

U2 - 10.1186/1750-1326-7-48

DO - 10.1186/1750-1326-7-48

M3 - Article

C2 - 22998728

AN - SCOPUS:84866519178

VL - 7

JO - Molecular Neurodegeneration

JF - Molecular Neurodegeneration

SN - 1750-1326

IS - 1

M1 - 48

ER -