Document Detail

Deficiency in ubiquitin ligase TRIM2 causes accumulation of neurofilament light chain and neurodegeneration.
MedLine Citation:
PMID:  18687884     Owner:  NLM     Status:  MEDLINE    
TRIM RING finger proteins have been shown to play an important role in cancerogenesis, in the pathogenesis of some human hereditary disorders, and in the defense against viral infection, but the function of the majority of TRIM proteins remains unknown. Here, we show that TRIM RING finger protein TRIM2, highly expressed in the nervous system, is an UbcH5a-dependent ubiquitin ligase. We further demonstrate that TRIM2 binds to neurofilament light subunit (NF-L) and regulates NF-L ubiquitination. Additionally, we show that mice deficient in TRIM2 have increased NF-L level in axons and NF-L-filled axonal swellings in cerebellum, retina, spinal cord, and cerebral cortex. The axonopathy is followed by progressive neurodegeneration accompanied by juvenile-onset tremor and ataxia. Our results demonstrate that TRIM2 is an ubiquitin ligase and point to a mechanism regulating NF-L metabolism through an ubiquitination pathway that, if deregulated, triggers neurodegeneration.
Martin Balastik; Francesco Ferraguti; André Pires-da Silva; Tae Ho Lee; Gonzalo Alvarez-Bolado; Kun Ping Lu; Peter Gruss
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-08-07
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  105     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2008 Aug 
Date Detail:
Created Date:  2008-08-20     Completed Date:  2008-09-16     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  12016-21     Citation Subset:  IM    
Max Planck Institute of Biophysical Chemistry, 37077 Goettingen, Germany.
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MeSH Terms
Cell Line
Gene Expression Regulation
Microscopy, Immunoelectron
Mutation / genetics
Neurons / metabolism*,  ultrastructure
Protein Binding
Proteins / genetics,  metabolism*
Time Factors
Ubiquitin / metabolism
Ubiquitin-Protein Ligases / deficiency*,  genetics,  metabolism*
Grant Support
Reg. No./Substance:
0/Proteins; 0/Trim2 protein, mouse; 0/Ubiquitin; EC Ligases

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