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Deficiency in ubiquitin ligase TRIM2 causes accumulation of neurofilament light chain and neurodegeneration
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Balastik, M., Ferraguti, F., Pires-da Silva, André Francisco, Lee, T. H., Alvarez-Bolado, G., Lu, K. P. and Gruss, P. (2008) Deficiency in ubiquitin ligase TRIM2 causes accumulation of neurofilament light chain and neurodegeneration. Proceedings of the National Academy of Sciences, Vol.105 (No.33). pp. 12016-12021. doi:10.1073/pnas.0802261105 ISSN 0027-8424.
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Official URL: http://dx.doi.org/10.1073/pnas.0802261105
Abstract
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.
Item Type: | Journal Article | ||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||
Journal or Publication Title: | Proceedings of the National Academy of Sciences | ||||
Publisher: | National Academy of Sciences | ||||
ISSN: | 0027-8424 | ||||
Official Date: | 2008 | ||||
Dates: |
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Volume: | Vol.105 | ||||
Number: | No.33 | ||||
Page Range: | pp. 12016-12021 | ||||
DOI: | 10.1073/pnas.0802261105 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access |
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