Deficiency in ubiquitin ligase TRIM2 causes accumulation of neurofilament light chain and neurodegeneration
2008; National Academy of Sciences; Volume: 105; Issue: 33 Linguagem: Inglês
10.1073/pnas.0802261105
ISSN1091-6490
AutoresMartin Balaštík, Francesco Ferraguti, André Pires‐daSilva, Tae Ho Lee, Gonzalo Ãlvarez-Bolado, Kun Ping Lu, Peter Gruß,
Tópico(s)Herpesvirus Infections and Treatments
ResumoTRIM 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.
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