Abstract
Protein quality-control, especially the removal of proteins with aberrant structures, has an important role in maintaining the homeostasis of non-dividing neural cells1. 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 process2,3. 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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Acknowledgements
We thank T. Kaneko, T. Kouno and K. Tatsumi for technical assistance. We also thank A. Yabashi, K. Kanno, F. Kaji and K. Ikeue for help with morphological analysis, J. Ezaki for discussion, and Z. Yue for critical reading of the manuscript. This work was supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Author contributions M.K. and T.C. generated Atg7flox/flox mice, and M.K. and J.I. performed most of the experiments to characterize Atg7flox/flox; nestin-Cre mice. S.W. performed histological and microscopic analyses, and S.M. performed the biochemical analysis of proteasome activity. M.K., S.W. and K.T. wrote the paper. All authors discussed the results and commented on the manuscript.
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Supplementary Figures
This file contains Supplementary Figures 1–4. Supplementary Figure 1 details a time course analysis of autophagic activity in brain of Atg7F/F:Nes mice. Supplementary Figure 2 details neural loss in the hippocampal pyramidal cell layer of Atg7F/F:Nes mice. Supplementary Figure 3 details ubiquitin-inclusions in neuronal axons. Supplementary Figure 4 details a schematic diagram of protein destruction pathways mediated by the proteasome and autophagy. (PDF 2963 kb)
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Komatsu, M., Waguri, S., Chiba, T. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006). https://doi.org/10.1038/nature04723
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DOI: https://doi.org/10.1038/nature04723
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