Mutations in the genes involved in the ubiquitin-proteasome system are known to cause accumulation of abnormal proteins in cells of the nervous system. A characteristic of Parkinson’s disease is the accumulation of aggregates called Lewy bodies. One of the causes of Lewy body formation is mutations in the gene for the ubiquitin-activating enzyme. A type of Parkinson’s disease without Lewy body pathology is also known. Gene mutations of an ubiquitin ligase called Parkin relate to the pathology of Parkinson’s disease. It localizes to and ubiquitinates depolarized damaged mitochondria, normally leading to their autophagic degradation. When autophagy is inhibited in neurons, damaged mitochondria accumulate and become a source of reactive oxygen species, causing injuries to the cells. Selective degradation of mitochondria by autophagy is called “mitophagy.” Some types of Parkinson’s disease are believed to be caused by defects in mitophagy.
ATG16L1 is a factor necessary for autophagosome formation. Interest in the association between mutations in ATG16L1 gene and the pathologies of Crohn’s disease and ulcerative colitis has been increasing. It is thought that Paneth cells (a type of intestinal cells) fail to mature when autophagy is impaired in intestinal epithelial cells, resulting in compromised intestinal barrier function and chronic inflammation.