# TIA1 Mutant Mouse Model Exhibits Motor Deficits and Neurodegenerative Characteristics of Amyotrophic Lateral Sclerosis

## TL;DR

A TIA1 mutant mouse model shows early signs of ALS, including motor neuron death and TDP-43 accumulation, before phosphorylation occurs.

## Contribution

The study introduces a TIA1Δ mouse model to investigate early, phosphorylation-independent TDP-43 pathology in ALS.

## Key findings

- Motor neuron death occurs before TDP-43 phosphorylation in TIA1Δ mice.
- TDP-43 accumulates and mislocalizes in the absence of phosphorylation in the model.
- The model exhibits neuroinflammation and muscle atrophy similar to ALS.

## Abstract

What are the main findings?
Motor neuron death in TIA1Δ mice occurs prior to detectable TDP-43 phosphorylation.TDP-43 accumulates and mislocalizes in the absence of phosphorylation in TIA1Δ mice, which may represent a speculative pre-aggregation-like disease stage.

Motor neuron death in TIA1Δ mice occurs prior to detectable TDP-43 phosphorylation.

TDP-43 accumulates and mislocalizes in the absence of phosphorylation in TIA1Δ mice, which may represent a speculative pre-aggregation-like disease stage.

What are the implications of the main findings?
The TIA1Δ mouse model provides a unique tool to dissect early, phosphorylation-independent toxic mechanisms potentially relevant to TDP-43 proteinopathy.Cautious interpretation of the TIA1Δ mouse model’s limitations is necessary when extrapolating its findings to human TDP-43 proteinopathy.

The TIA1Δ mouse model provides a unique tool to dissect early, phosphorylation-independent toxic mechanisms potentially relevant to TDP-43 proteinopathy.

Cautious interpretation of the TIA1Δ mouse model’s limitations is necessary when extrapolating its findings to human TDP-43 proteinopathy.

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.