*2.1. Neurodegenerative Diseases*

Various quality control systems enable the production of high-quality proteins in the cell. The endoplasmic reticulum is equipped with a protein quality control mechanism termed endoplasmic reticulum-associated degradation (ERAD), in which the ubiquitin–proteasome system (UPS) plays a central role [1]. The UPS selectively and rapidly degrades and removes abnormal proteins by adding ubiquitin chains [2]. Recently, a new quality control mechanism called mitochondrial protein translocation-associated degradation (mitoTAD) has been discovered in yeas<sup>t</sup> [3]. It would be interesting to determine whether such a sophisticated quality control mechanism is preserved in mammals. The accumulation of dysfunctional proteins has been observed in many neurodegenerative diseases, and it has become clear that it is deeply involved in their pathogenesis. The increase in dysfunctional proteins due to mutations in the causative gene and the decrease in proteasome activity with aging are thought to be the main pathogenic factors. The accumulation of dysfunctional proteins in cells leads to a decrease in proteasome activity, suggesting the presence of a downward spiral that further promotes the accumulation of aggregated proteins [4]. It has been reported that such highly aggregated dysfunctional proteins can also accumulate in mitochondria and impair their function [5]. As an example, mutant superoxide dismutase-1 (mSOD1), one of the gene products responsible for amyotrophic lateral sclerosis (ALS), aggregates due to its conformational changes, accumulates in mitochondria, and inhibits mitochondrial protein transport, thereby impairing mitochondrial function. In addition, in spinal cerebellar degeneration, such as polyglutamine disease, the abnormal elongation of the polyglutamine chain resulting in conformational changes leading to accumulation of the protein PolyQ in the nucleus and mitochondria, and reduces mitochondrial function, which is thought to be one of the mechanisms of neuropathy. We reported that MITOL specifically ubiquitinates and promotes the proteasomal degradation of the misfolded proteins mSOD1 and PolyQ as substrates [6,7]. MITOL has a disordered domain in its C-terminal region, which may recognize denatured proteins. This suggests that MITOL is involved in mitochondrial quality control by eliminating dysfunctional proteins from the mitochondria. However, it is controversial whether MITOL recognizes target proteins in the process of aggregation or after their aggregation.
