Loss of autophagy in the central nervous system causes neurodegeneration in mice

Abstract

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. One of two papers showing that loss of autophagy in the central nervous system of mice causes the accumulation of protein aggregates in inclusion bodies, neurodegeneration and premature death of the mice. This demonstrates that continuous clearance of cellular components is essential for proper housekeeping and vital to keep the neurons in tiptop shape. 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.