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The Use of Primary Human Fibroblasts for Monitoring Mitochondrial Phenotypes in the Field of Parkinson's Disease
Published on: October 3, 2012
Dopamine covalently modifies and functionally inactivates parkin
Matthew J LaVoie1, Beth L Ostaszewski, Andreas Weihofen
1Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, HIM 7th Floor, Boston, Massachusetts 02115, USA. mlavoie@rics.bwh.harvard.edu
Nature Medicine
|October 18, 2005
Summary
Dopamine modifies parkin, a protein linked to Parkinson disease, making it insoluble and inactive. This modification occurs in sporadic Parkinson disease, suggesting a new mechanism for neurodegeneration.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Mutations in PARK2 (parkin) cause early-onset parkinsonism via degeneration of specific neurons.
- The role of parkin in sporadic Parkinson disease (PD) is not well understood.
Purpose of the Study:
- To investigate the role of dopamine in parkin function and its potential involvement in sporadic Parkinson disease.
Main Methods:
- Studied dopamine modification of parkin in living dopaminergic cells.
- Assessed parkin solubility and E3 ubiquitin ligase activity.
- Analyzed parkin modification in human brain tissue from individuals with and without sporadic PD using a novel biochemical method.
Main Results:
- Dopamine covalently modifies parkin, increasing its insolubility and inactivating its E3 ubiquitin ligase function.
- Parkin showed decreased solubility in the brains of individuals with sporadic PD, consistent with functional inactivation.
- Catechol-modified parkin was detected specifically in the substantia nigra of normal human brain.
Conclusions:
- Parkin is vulnerable to dopamine modification, which inactivates its function.
- This dopamine-induced inactivation of parkin may contribute to progressive neurodegeneration in dopaminergic neurons during aging and sporadic Parkinson disease.
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These groups modify specific amino acids in a protein.
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