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Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice

Abstract

Autophagy is an intracellular bulk degradation process through which a portion of the cytoplasm is delivered to lysosomes to be degraded1,2,3,4. 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 diseases5,6,7,8. 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.

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Figure 1: Behavioural abnormalities in mice lacking Atg5 in the nervous system.
Figure 2: Neuronal degeneration in Atg5 flox/ flox ; nestin- Cre mice.
Figure 3: Ubiquitin-positive inclusions in Atg5 -deficient neurons.
Figure 4: Accumulation of diffuse ubiquitinated proteins in autophagy-defective cells.

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Acknowledgements

We thank H. Neko, M. Miwa and Y. Kabeya for technical assistance. We also thank J. Miyazaki for the donation of CAG-Cre transgenic mice, T. Yoshimori for the anti-LC3 antibody, E. Yamada for histological examination, M. Yuzaki for the rotarod analysis, and A. Kuma for discussion. We thank Z. Yue for critical reading of the manuscript. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The authors thank the Yamada Science Foundation and the Cell Science Research Foundation for their financial support. Author Contributions T.H. performed most of the experiments to characterize the neuron-specific knockout mice. M.M. analysed Atg5-/- mice. K.N., Y.N., R.S.-M. and M.Y. generated Atg5flox chimaeric mice. A.Y. performed electron microscopy. K.M. and I.S. performed histological analysis. H.O. provided nestin-Cre mice and participated in manuscript preparation. N.M. conceived the experiments and generated the targeting vector. T.H. and N.M. wrote the paper.

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Correspondence to Noboru Mizushima.

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Hara, T., Nakamura, K., Matsui, M. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006). https://doi.org/10.1038/nature04724

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