Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
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Target Concepts:
Gene/Protein
Disease
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Enzyme
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Query: UMLS:C0004134 (
ataxia
)
15,886
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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.
...
PMID:Deficiency in ubiquitin ligase TRIM2 causes accumulation of neurofilament light chain and neurodegeneration. 1868 84
We analyzed Trim2
A/A
mice, generated by CRISPR-Cas9, which have a recessive, null mutation of Trim2. Trim2
A/A
mice develop
ataxia
that is associated with a severe loss of cerebellar Purkinje cells and a peripheral neuropathy. Myelinated axons in the CNS, including those in the deep cerebellar nuclei, have focal enlargements that contain mitochondria and neurofilaments. In the PNS, there is a loss of myelinated axons, particularly in the most distal nerves. The pathologically affected neuronal populations - primary sensory and motor neurons as well as cerebellar Purkinje cells - express
TRIM2
, suggesting that loss of
TRIM2
in these neurons results in cell autonomous effects on their axons. In contrast, these pathological findings were not found in a second strain of Trim2 mutant mice (Trim2
C/C
), which has a partial deletion in the RING domain that is needed for ubiquitin ligase activity. Both the Trim2
A
and the Trim2
C
alleles encode mutant
TRIM2
proteins with reduced ubiquitination activity. In sum, Trim2
A/A
mice are a genetically authentic animal model of a recessive axonal neuropathy of humans, apparently for a function that does not depend on the ubiquitin ligase activity.
...
PMID:A recessive Trim2 mutation causes an axonal neuropathy in mice. 3220 55
