1. Department of Bioregulation and Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan
2. Mouse Genome Technology Laboratory, Mitsubishi Kagaku Institute of Life Sciences, Tokyo 194-8511, Japan
3. Department of Basic Biology, School of Life Science, the Graduate University for Advanced Studies, Okazaki 444-8585, Japan
4. Department of Cell Biology, National Institute for Basic Biology, Okazaki 444-8585, Japan
5. Department of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Japan
6. Brain Research Institute, Niigata University, Niigata 951-8510, Japan
7. Department of Pathology, Tsurumi University School of Dental Medicine, Yokohama 230-8501, Japan
8. Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan
9. SORST and
10. PRESTO, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan

Correspondence to: Noboru Mizushima^1,10 Correspondence and requests for materials should be addressed to to N.M. (Email: nmizu@rinshoken.or.jp).

Abstract

Autophagy is an intracellular bulk degradation process through which a portion of the cytoplasm is delivered to lysosomes to be degraded^{1, 2, 3, 4}. Although the primary role of autophagy in many organisms is in adaptation to starvation, autophagy is also thought to be important for normal turnover of cytoplasmic contents, particularly in quiescent cells such as neurons. Autophagy may have a protective role against the development of a number of neurodegenerative diseases^{5, 6, 7, 8}. Here we report that loss of autophagy causes neurodegeneration even in the absence of any disease-associated mutant proteins. Mice deficient for Atg5 (autophagy-related 5) specifically in neural cells develop progressive deficits in motor function that are accompanied by the accumulation of cytoplasmic inclusion bodies in neurons. In Atg5^-/- cells, diffuse, abnormal intracellular proteins accumulate, and then form aggregates and inclusions. These results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration.

1. Department of Bioregulation and Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan
2. Mouse Genome Technology Laboratory, Mitsubishi Kagaku Institute of Life Sciences, Tokyo 194-8511, Japan
3. Department of Basic Biology, School of Life Science, the Graduate University for Advanced Studies, Okazaki 444-8585, Japan
4. Department of Cell Biology, National Institute for Basic Biology, Okazaki 444-8585, Japan
5. Department of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Japan
6. Brain Research Institute, Niigata University, Niigata 951-8510, Japan
7. Department of Pathology, Tsurumi University School of Dental Medicine, Yokohama 230-8501, Japan
8. Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan
9. SORST and
10. PRESTO, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan

Correspondence to: Noboru Mizushima^1,10 Correspondence and requests for materials should be addressed to to N.M. (Email: nmizu@rinshoken.or.jp).

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