A recessive Trim2 mutation causes an axonal neuropathy in mice

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• The gene Tri-methylguanosine 2 (TRIM2) plays a role in neuronal function.
• Mutations in TRIM2 are implicated in certain neurological disorders.

Purpose of the Study:

• To investigate the function of TRIM2 in the nervous system using a novel mouse model.
• To determine the role of TRIM2's ubiquitin ligase activity in its neurological functions.

Main Methods:

• CRISPR-Cas9 gene editing was used to generate Trim2^A/A and Trim2^C/C mutant mice.
• Phenotypic analysis included assessment of ataxia, peripheral neuropathy, and axonal integrity in the central and peripheral nervous systems.
• Immunohistochemistry and biochemical assays were employed to evaluate TRIM2 protein levels and activity.

Main Results:

• Trim2^A/A mice, lacking functional TRIM2, developed ataxia, Purkinje cell loss, and peripheral neuropathy with axonal enlargements and degeneration.
• These pathological changes were observed in neurons expressing TRIM2, suggesting cell-autonomous effects.
• Trim2^C/C mice, with impaired but not null TRIM2 ubiquitin ligase activity, did not exhibit these severe phenotypes.
• Both mutant alleles resulted in reduced TRIM2 ubiquitination activity.

Conclusions:

• Trim2^A/A mice represent a valid animal model for human recessive axonal neuropathies.
• TRIM2 is essential for maintaining axonal integrity in both the central and peripheral nervous systems.
• The neuropathy associated with TRIM2 deficiency appears to be independent of its ubiquitin ligase activity.