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PMID: 25611507 Published · ppublish English Journal Article Research Support, N.I.H., Intramural Review

The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease.

Neuron ·Vol. 85 ·No. 2 ·2015-01-21 ·Pages 257-73

Pickrell AM, Youle RJ

Abstract

Understanding the function of genes mutated in hereditary forms of Parkinson's disease yields insight into disease etiology and reveals new pathways in cell biology. Although mutations or variants in many genes increase the susceptibility to Parkinson's disease, only a handful of monogenic causes of parkinsonism have been identified. Biochemical and genetic studies reveal that the products of two genes that are mutated in autosomal recessive parkinsonism, PINK1 and Parkin, normally work together in the same pathway to govern mitochondrial quality control, bolstering previous evidence that mitochondrial damage is involved in Parkinson's disease. PINK1 accumulates on the outer membrane of damaged mitochondria, activates Parkin's E3 ubiquitin ligase activity, and recruits Parkin to the dysfunctional mitochondrion. Then, Parkin ubiquitinates outer mitochondrial membrane proteins to trigger selective autophagy. This review covers the normal functions that PINK1 and Parkin play within cells, their molecular mechanisms of action, and the pathophysiological consequences of their loss.

MeSH Terms
Humans Mitochondria/metabolism Mitophagy/physiology Parkinson Disease/genetics,metabolism Parkinsonian Disorders/genetics Protein Kinases/genetics,metabolism Proteolysis Ubiquitin-Protein Ligases/genetics,metabolism
Chemicals
Ubiquitin-Protein Ligases parkin protein Protein Kinases PTEN-induced putative kinase
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Pickrell Alicia M
Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, MD 20892, USA.
Youle Richard J
Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, MD 20892, USA. Electronic address: youler@ninds.nih.gov.
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Article Info
Journal
Neuron
Abbr.
Neuron
ISSN
1097-4199
DOI
10.1016/j.neuron.2014.12.007
Email
youler@ninds.nih.gov
Published
2015-01-21
Pages
257-73
Language
English
Region
United States
NLM ID
8809320
PMCID
PMC4764997
Subset
IM
Grants
Intramural NIH HHS · Z01 NS002859-16 · United States
External Links
PubMed source DOI: 10.1016/j.neuron.2014.12.007 PMC Full Text View journal details
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