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Published on: October 6, 2015
TIA1 Mutant Mouse Model Exhibits Motor Deficits and Neurodegenerative Characteristics of Amyotrophic Lateral
Li-Hong Mao1, Yu-Ning Song2, Jing-Qi Zhang1
1Laboratory of Research in Parkinson's Disease and Related Disorders, Health Sciences Institute, China Medical University, Shenyang 110122, China.
Background:
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that primarily affects the motor neurons. T cell intracellular antigen 1 (TIA1) is a risk gene for ALS pathogenesis. To elucidate TIA1-mediated disease mechanisms, a mouse model recapitulating clinical and pathological features of ALS is needed. TIA1 mutations are rare in human ALS, and mutations are heterozygous, while this study uses a homozygous TIA1 mutant mouse model to amplify pathogenic effects for experimental tractability.
Methods:
To explore the mechanisms by which mutant TIA1 causes ALS neurodegeneration, we generated a TIA1 mutant mouse by introducing ALS-causing mutations into the endogenous animal via cytosine base editors. Next, behavioral experiments (open-field and rotarod tests) assessed motor function and analyzed pathologies using morphological assessments.
Results:
Our TIA1Δ mouse model phenocopies select pivotal features of ALS, including TAR DNA-binding protein 43 (TDP-43) accumulation, motor neuron loss, neuroinflammation in the lumbar spinal cord, and muscle atrophy. Notably, this homozygous mutation design with reduced TIA1 expression differs from human heterozygous TIA1 mutations.
Conclusions:
This work provides a foundation for understanding the TIA1-ALS relationship and for developing strategies to treat this intractable neurodegenerative disorder. Caution is warranted extrapolating findings to human ALS pathogenesis due to model design differences.
