Loss of autophagy in the central nervous system causes neurodegeneration in mice
Abstract
Protein quality-control, especially the removal of proteins with aberrant structures, has an important role in maintaining the homeostasis of non-dividing neural cells. In addition to the ubiquitin-proteasome system, emerging evidence points to the importance of autophagy--the bulk protein degradation pathway involved in starvation-induced and constitutive protein turnover--in the protein quality-control process. However, little is known about the precise roles of autophagy in neurons. Here we report that loss of Atg7 (autophagy-related 7), a gene essential for autophagy, leads to neurodegeneration. We found that mice lacking Atg7 specifically in the central nervous system showed behavioural defects, including abnormal limb-clasping reflexes and a reduction in coordinated movement, and died within 28 weeks of birth. Atg7 deficiency caused massive neuronal loss in the cerebral and cerebellar cortices. Notably, polyubiquitinated proteins accumulated in autophagy-deficient neurons as inclusion bodies, which increased in size and number with ageing. There was, however, no obvious alteration in proteasome function. Our results indicate that autophagy is essential for the survival of neural cells, and that impairment of autophagy is implicated in the pathogenesis of neurodegenerative disorders involving ubiquitin-containing inclusion bodies.
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Proteasome function was normal in autophagy-deficient brain.
“Proteasome function was found to be normal in autophagydeficient brain (Komatsu et al., 2006).”
From Depletion of 26S Proteasomes in Mouse Brain Neurons Causes Neurodegeneration and Lewy-Like Inclusions Resembling Human Pale Bodies (2008) · cites this paper as Komatsu et al., 2006
Autophagy could protect cells from death, especially in motor neurons.
“Autophagy could protect cells from death (Hara et al., 2006; Komatsu et al., 2006), especially in motor neurons (Barmada et al., 2014).”
From Downregulation of MicroRNA-193b-3p Promotes Autophagy and Cell Survival by Targeting TSC1/mTOR Signaling in NSC-34 Cells (2017) · cites this paper as Komatsu et al., 2006
Autophagy protects cells from death, especially motor neurons.
“Autophagy could protect cells from death (Hara et al., 2006; Komatsu et al., 2006), especially in the case of motor neurons (Barmada et al., 2014).”
From Downregulation of MicroRNA-193b-3p Promotes Autophagy and Cell Survival by Targeting TSC1/mTOR Signaling in NSC-34 Cells (2017) · cites this paper as Komatsu et al., 2006
Autophagy is protective for neuronal survival in neurodegenerative diseases.
“Autophagy is now recognized as protective for neuronal survival in neurodegenerative diseases (Hara et al., 2006; Komatsu et al., 2006; Lee, 2012).”
From Downregulation of MicroRNA-193b-3p Promotes Autophagy and Cell Survival by Targeting TSC1/mTOR Signaling in NSC-34 Cells (2017) · cites this paper as Komatsu et al., 2006
Reduced basal autophagy in the mouse nervous system leads to neurodegeneration.
“Reduced basal autophagy in the mouse nervous system similarly leads to neurodegeneration (54,55).”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [55]
Basal autophagy in neurons is essential for maintaining long-term neuronal health, since disruption of baseline autophagic activity in vivo causes neurodegeneration and the accumulation of inclusions containing polyubiquitinated proteins.
“Basal autophagy in neurons is essential for maintaining long-term neuronal health, since disruption of baseline autophagic activity in vivo causes neurodegeneration and the accumulation of inclusions containing polyubiquitinated proteins [380,381].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [380]
Unlike neurons, astrocytic loss of Atg7 or Atg5 is insufficient to cause cell death or the accumulation of misfolded and ubiquitinated proteins.
“Unlike neurons, astrocytic loss of Atg7 or Atg5 is insufficient to cause cell death or the accumulation of misfolded and ubiquitinated proteins [380,381]”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [380]
Astrocytes have greater proteostatic reserve compared to neurons.
“implying greater proteostatic reserve in astrocytes compared to neurons.”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [380]
A deficit in autophagy in Atg7CKO mice was confirmed by western blot of conjugated ATG5-12, p62, and LC3-II and by immunolabel of p62 and ubiquitin.
“A deficit in autophagy was confirmed by western blot analysis of conjugated ATG5-12, p62 and LC3-II proteins (Fig 5A) and by immunolabel of p62 and ubiquitin (Ub) (Figs 5B and 6A), proteins that form aggregates after autophagy inhibition (Komatsu et al., 2006; Komatsu et al., 2007).”
From Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits (2014) · cites this paper as Komatsu et al., 2006
Atg7 is an E1-like activating enzyme required for autophagosome formation.
“Atg7 is an E1-like activating enzyme required for autophagosome formation (Komatsu et al., 2006).”
From Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits (2014) · cites this paper as Komatsu et al., 2006
Mice that developmentally lack autophagy in the neuronal compartment display shortened lifespan and early-onset neurodegenerative pathologies associated with pathological accumulation of proteinaceous aggregates in multiple neuronal populations.
“mice that developmentally lack autophagy in the neuronal compartment display shortened lifespan and early‐onset neurodegenerative pathologies (whose severity varies depending on the targeted gene), associated with the pathological accumulation of proteinaceous aggregates in multiple neuronal populations (Hara et al, 2006; Komatsu et al, 2006; Metcalf et al, 2012).”
From Autophagy in major human diseases (2021) · cites this paper as Komatsu et al, 2006
Brain-specific deletion of Atg5 or Atg7 in mice reveals a critical role of autophagy in the removal of aggregated proteins.
“Although the phenotypes of mice harboring brain-specific deletion of Atg5 or Atg7 reveal the critical role of autophagy in the removal of aggregated proteins7,8”
From Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice (2018) · cites this paper as [8]
Brain-specific conditional knockouts of Atg5 and Atg7 show shortened lifespan and accelerated age-related neuronal degeneration.
“Nonetheless, two subsequent studies that used brain-specific conditional knockouts of Atg5 and Atg7 revealed that, in these animals, the absence of autophagy leads to a shortened lifespan and an accelerated form of age-related neuronal degeneration 80, 81 .”
From The common biology of cancer and ageing (2007) · cites this paper as [80]
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- Authors
- Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J.-I., Tanida, I., Ueno, T., Koike, M., Uchiyama, Y., Kominami, E., & Tanaka, K.
- Affiliations
- Tokyo Metropolitan Institute of Medical Science (JP)
- Fukushima Medical University (JP)
- Juntendo University (JP)
- The University of Osaka (JP)
- Corresponding author
- Tanaka, Keiji
- ORCID
- Venue
- Nature
- Published
- 2006-04-19
- Volume
- 441
- Issue
- 7095
- Pages
- 880-884
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2022812113
- Cited by
- 3,500
- References
- 30
- Citations by year
- 2026: 68 · 2025: 113 · 2024: 111 · 2023: 117 · 2022: 164 · 2021: 209 · 2020: 215 · 2019: 216 · 2018: 191 · 2017: 206 · 2016: 196 · 2015: 191 · 2014: 191 · 2013: 210 · 2012: 201
- FWCI
- 123.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- autophagy, neurodegeneration, ATG7, protein quality control, polyubiquitinated proteins, neuronal survival, central nervous system, neurodegenerative diseases, proteasome, brain aging, cerebellar cortex, cerebral cortex
- MeSH terms
- Autophagy-Related Protein 7, Animals, Autophagy, Inclusion Bodies, Central Nervous System, Cerebellum, Cerebral Cortex, Intermediate Filament Proteins, Mice, Transgenic, Microtubule-Associated Proteins, Nerve Tissue Proteins, Neurons, Survival Rate, Cell Death, Neurodegenerative Diseases, Ubiquitin, Proteasome Endopeptidase Complex, Mice, Nestin
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