How does parkin ligate ubiquitin to Parkinson's disease?
Open Access
- 1 July 2004
- journal article
- review article
- Published by Springer Nature in EMBO Reports
- Vol. 5 (7), 681-685
- https://doi.org/10.1038/sj.embor.7400188
Abstract
Recessive mutations in the human PARKIN gene are the most common cause of hereditary parkinsonism, which arises from the degeneration of dopaminergic neurons in the substantia nigra. However, the molecular mechanisms by which the loss of parkin causes dopaminergic neurodegeneration are not well understood. Parkin is an enzyme that ubiquitinates several candidate substrate proteins and thereby targets them for proteasomal degradation. Hypothesis‐driven searches have led to the discovery of aggregation‐prone protein substrates of parkin. Moreover, the enzyme is upregulated when under unfolded protein stress. Thus, loss‐of‐function mutations of parkin might impair the removal of potentially toxic protein aggregates. However, the limited neuropathological information that is available from parkin‐proven patients, as well as the recent knockout of the parkin gene in fruit flies and mice, may indicate a more complex disease mechanism, possibly involving the misfolding of parkin itself or of additional substrates. The risk factors that predispose dopaminergic neurons to degenerate on parkin failure are yet to be identified.Keywords
This publication has 49 references indexed in Scilit:
- Alpha‐synuclein in Parkinson's disease: Light from two new anglesAnnals of Neurology, 2004
- Parkin genetics: one model for Parkinson's diseaseHuman Molecular Genetics, 2004
- A Product of the Human Gene Adjacent to parkin Is a Component of Lewy Bodies and Suppresses Pael Receptor-induced Cell DeathPublished by Elsevier ,2003
- Parkin is recruited into aggresomes in a stress-specific manner: over-expression of parkin reduces aggresome formation but can be dissociated from parkin's effect on neuronal survivalHuman Molecular Genetics, 2003
- Parkin is recruited to the centrosome in response to inhibition of proteasomesJournal of Cell Science, 2003
- The autosomal recessive juvenile Parkinson disease gene product, parkin, interacts with and ubiquitinates synaptotagmin XIHuman Molecular Genetics, 2003
- A superfamily of protein tags: ubiquitin, SUMO and related modifiersTrends in Biochemical Sciences, 2003
- Parkin Localizes to the Lewy Bodies of Parkinson Disease and Dementia with Lewy BodiesThe American Journal of Pathology, 2002
- Ubiquitination of a New Form of α-Synuclein by Parkin from Human Brain: Implications for Parkinson's DiseaseScience, 2001
- Alpha-synuclein and neurodegenerative diseasesNature Reviews Neuroscience, 2001