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PMID: 19033459 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Pruning and loss of excitatory synapses by the parkin ubiquitin ligase.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 105 ·No. 49 ·2008-12-09 ·Pages 19492-7

Helton TD, Otsuka T, Lee MC, Mu Y, Ehlers MD

Abstract

Mutations in the PARK2 gene cause hereditary Parkinson disease (PD). The PARK2 gene product, termed parkin, is an E3 ubiquitin ligase that mediates the transfer of ubiquitin onto diverse substrate proteins. Despite progress in defining the molecular properties and substrates of parkin, little is known about its physiological function. Here, we show that parkin regulates the function and stability of excitatory glutamatergic synapses. Postsynaptic expression of parkin dampens excitatory synaptic transmission and causes a marked loss of excitatory synapses onto hippocampal neurons. Conversely, knockdown of endogenous parkin or expression of PD-linked parkin mutants profoundly enhances synaptic efficacy and triggers a proliferation of glutamatergic synapses. This proliferation is associated with increased vulnerability to synaptic excitotoxicity. Thus, parkin negatively regulates the number and strength of excitatory synapses. Increased excitatory drive produced by disruption of parkin may contribute to the pathophysiology of PD.

MeSH Terms
Animals Cells, Cultured Cerebral Cortex/cytology Excitatory Postsynaptic Potentials/physiology Glutamic Acid/metabolism Hippocampus/cytology Mutation Neurons/pathology,physiology Neurotoxins/metabolism Parkinson Disease/metabolism,pathology,physiopathology Patch-Clamp Techniques Rats Synapses/enzymology,pathology Synaptic Transmission/physiology Ubiquitin-Protein Ligases/genetics,metabolism
Chemicals
Neurotoxins Glutamic Acid Ubiquitin-Protein Ligases parkin protein
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Helton Thomas D
Department of Neurobiology, Duke University Medical Center, Durham, NC 27710, USA.
Otsuka Takeshi
Lee Ming-Chia
Mu Yuanyue
Ehlers Michael D
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0802280105
Published
2008-12-09
Epub
2008-00-25
Pages
19492-7
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2614788
Subset
IM
Grants
Howard Hughes Medical Institute · United States
External Links
PubMed source DOI: 10.1073/pnas.0802280105 PMC Full Text View journal details
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