Loss of autophagy in the central nervous system causes neurodegeneration in mice (original) (raw)

Nature volume 441, pages 880–884 (2006)Cite this article

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 Atg7 flox/flox mice, and M.K. and J.I. performed most of the experiments to characterize Atg7 flox/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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Author notes

  1. Satoshi Waguri
    Present address: Department of Anatomy and Histology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan
  2. Masaaki Komatsu and Satoshi Waguri: *These authors contributed equally to this work

Authors and Affiliations

  1. Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo, 113-8613, Japan
    Masaaki Komatsu, Tomoki Chiba, Shigeo Murata, Jun-ichi Iwata & Keiji Tanaka
  2. Department of Biochemistry, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan
    Masaaki Komatsu, Jun-ichi Iwata, Isei Tanida, Takashi Ueno & Eiki Kominami
  3. Department of Cell Biology and Neurosciences, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan
    Satoshi Waguri, Masato Koike & Yasuo Uchiyama

Authors

  1. Masaaki Komatsu
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  2. Satoshi Waguri
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  3. Tomoki Chiba
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  4. Shigeo Murata
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  5. Jun-ichi Iwata
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  6. Isei Tanida
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  7. Takashi Ueno
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  8. Masato Koike
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  9. Yasuo Uchiyama
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  10. Eiki Kominami
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  11. Keiji Tanaka
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Correspondence toKeiji Tanaka.

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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 Atg7 F/F:Nes mice. Supplementary Figure 2 details neural loss in the hippocampal pyramidal cell layer of Atg7 F/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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Editorial Summary

A tidy cell is a healthy cell

Two papers this week suggest that the process of protein degradation and clearance of cellular components may be more important in maintaining the health of the nervous system than was thought. Both groups show that inhibition of autophagy in mouse brain cells results in neurodegeneration and early death. Autophagy, the protein degradation and recycling of cellular components, is important for the normal growth and development of a cell. The finding that the continual clearance of cellular components is essential for maintaining neuronal health should open up new avenues of research into the nature of neurodegenerative diseases.

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