Intracellular quality control by autophagy: how does autophagy prevent neurodegeneration?
Autophagy is an intracellular bulk degradation process, through which a portion of cytoplasm is delivered to lysosomes to be degraded. In many organisms, the primary role of autophagy is adaptation to starvation. However, we have found that autophagy is also important for intracellular protein quality control. Atg5(-/-) mice die shortly after birth due, at least in part, to nutrient deficiency. These mice also exhibit an intracellular accumulation of protein aggregates in neurons and hepatocytes. We now report the generation of neural cell-specific Atg5-deficient mice. Atg5( flox/flox);Nestin-Cre mice show progressive deficits in motor function and degeneration of some neural cells. In autophagy-deficient cells, diffuse accumulation of abnormal proteins occurs, followed by the generation of aggregates and inclusions. This study emphasizes the point that basal autophagy is important even in individuals who do not express neurodegenerative disease-associated mutant proteins. Furthermore, the primary targets of autophagy are diffuse cytosolic proteins, not protein aggregates themselves.
Mizushima
Noboru
N
Department of Bioregulation and Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan. nmizu.phy2@tmd.ac.jp
Hara
Taichi
T
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D002479:Inclusion Bodies / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism
C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D025801:Ubiquitin