1. Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan
2. Department of Biochemistry, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
3. Department of Cell Biology and Neurosciences, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
4. †Present address: Department of Anatomy and Histology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan
5. *These authors contributed equally to this work

Correspondence to: Keiji Tanaka¹ Correspondence and requests for materials should be addressed to K.T. (Email: tanakak@rinshoken.or.jp).

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 process^{2, 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.

1. Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Bunkyo-ku, Tokyo 113-8613, Japan
2. Department of Biochemistry, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan
3. Department of Cell Biology and Neurosciences, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
4. †Present address: Department of Anatomy and Histology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan
5. *These authors contributed equally to this work

Correspondence to: Keiji Tanaka¹ Correspondence and requests for materials should be addressed to K.T. (Email: tanakak@rinshoken.or.jp).

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