Morphological analysis of autophagy in axonal degeneration in gracile axonal dystrophy mice.

Gracile axonal dystrophy (gad) mutant mice present with autosomal recessive inherited sensory ataxia in the early stages, followed by age-dependent motor ataxia. This phenotype is caused by a mutation in the ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCH-L1) gene and leads to a lack of expression of UCH-L1 protein, ubiquitin-proteasome which is related to the autophagy pathway and the ubiquitin-proteasome system (UPS). To elucidate the pathophysiology of abnormal protein accumulation in gad mice, we focused on macroautophagy. Using electron microscopy, we detected a double-membrane structure, which was characteristic of autophagosomes, in gad mice. In addition, in immunohistochemistry to investigate the expression levels of autophagy-related proteins in the gracile nuclei of the gad mouse, we found upregulation of LC3 and p62 but not LAMP-2A. These results suggested that a lack of UCH-L1 expression might induce the formation of autophagosomes, but the resulting autophagy flux might be disturbed.