Deficiency in ubiquitin ligase TRIM2 causes accumulation of neurofilament light chain and neurodegeneration.
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.
Balastik
Martin
M
Max Planck Institute of Biophysical Chemistry, 37077 Goettingen, Germany. mbalasti@bidmc.harvard.edu
Ferraguti
Francesco
F
Pires-da Silva
André
A
Lee
Tae Ho
TH
Alvarez-Bolado
Gonzalo
G
Lu
Kun Ping
KP
Gruss
Peter
P
D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D051379:Mice; D016253:Microscopy, Immunoelectron; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*
D011506:Proteins; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; C485687:Trim2 protein, mouse; D044767:Ubiquitin-Protein Ligases