[The ubiquitin-proteasome system and neurodegeneration]
- PMID: 12235799
[The ubiquitin-proteasome system and neurodegeneration]
Abstract
Many studies have suggested the ubiquitin-proteasome system played an essential role in the pathogenesis of neurodegenerative disorders. In 1999, we provided evidence that a mutation of the system could directly cause neurodegeneration using the gad mouse. Namely, we identified the gad mutation was caused by an intragenic deletion of a gene encoding ubiquitin C-terminal hydrolase 1(UCH-L1), which is a member of de-ubiquitinating enzyme family. In human, missense mutation of UCH-L1 gene was reported in a German family with Parkinson's disease. As well, the parkin gene product was revealed to be an E3 ubiquitin ligase which recognize a form of alpha-synuclein as a substrate. Thus, the investigation of the ubiquitin-proteasome system should provide a clue for understanding neurodegeneration. We have characterized UCH-L1 and identified candidates of endogenous substrates as well as interacting proteins of UCH-L1. In addition, we found amount of monomeric ubiquitin was decreased in the brain of the gad mouse compared with wild type mice. We have also tried to develop "protein therapy" using UCH-L1 protein with TAT sequence. We observed the protein was delivered to brain after intraperitoneal injection in the wild type mouse. This approach would provide a new therapeutic strategy for neurodegeneration.
Similar articles
-
Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice.Nat Genet. 1999 Sep;23(1):47-51. doi: 10.1038/12647. Nat Genet. 1999. PMID: 10471497
-
UCH-L1 aggresome formation in response to proteasome impairment indicates a role in inclusion formation in Parkinson's disease.J Neurochem. 2004 Jul;90(2):379-91. doi: 10.1111/j.1471-4159.2004.02485.x. J Neurochem. 2004. PMID: 15228595
-
[Parkinson's disease: what have we learned from the genes responsible for familial forms?].Med Sci (Paris). 2003 May;19(5):613-9. doi: 10.1051/medsci/2003195613. Med Sci (Paris). 2003. PMID: 12836396 Review. French.
-
Loss of Uch-L1 and Uch-L3 leads to neurodegeneration, posterior paralysis and dysphagia.Hum Mol Genet. 2001 Sep 1;10(18):1963-70. doi: 10.1093/hmg/10.18.1963. Hum Mol Genet. 2001. PMID: 11555633
-
Proteolytic stress: a unifying concept for the etiopathogenesis of Parkinson's disease.Ann Neurol. 2003;53 Suppl 3:S73-84; discussion S84-6. doi: 10.1002/ana.10512. Ann Neurol. 2003. PMID: 12666100 Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Other Literature Sources
Medical
Research Materials
Miscellaneous