TIA1 Mutant Mouse Model Exhibits Motor Deficits and Neurodegenerative Characteristics of Amyotrophic Lateral Sclerosis
(2026) In Cells 15(5).- Abstract
Highlights: 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. 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. Background: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that primarily affects the motor... (More)
Highlights: 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. 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. 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.
(Less)
- author
- organization
- publishing date
- 2026-03
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- amyotrophic lateral sclerosis, mouse model, neurodegenerative disease, neuroinflammation, TDP-43, TIA1
- in
- Cells
- volume
- 15
- issue
- 5
- article number
- 420
- publisher
- MDPI AG
- external identifiers
-
- scopus:105032686926
- pmid:41827855
- ISSN
- 2073-4409
- DOI
- 10.3390/cells15050420
- language
- English
- LU publication?
- yes
- id
- f80fb3f1-b77d-4aaa-9f5d-938ef25b8b2e
- date added to LUP
- 2026-04-21 15:07:06
- date last changed
- 2026-06-02 17:55:44
@article{f80fb3f1-b77d-4aaa-9f5d-938ef25b8b2e,
abstract = {{<p>Highlights: 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. 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. 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.</p>}},
author = {{Mao, Li Hong and Song, Yu Ning and Zhang, Jing Qi and Shao, Yun Ting and Wang, Zhang Li and Yang, Na and Zhang, Wen Xuan and Zhang, Ying Rui and Gao, Xiao Yan and Li, Jia Yi and Yuan, Lin}},
issn = {{2073-4409}},
keywords = {{amyotrophic lateral sclerosis; mouse model; neurodegenerative disease; neuroinflammation; TDP-43; TIA1}},
language = {{eng}},
number = {{5}},
publisher = {{MDPI AG}},
series = {{Cells}},
title = {{TIA1 Mutant Mouse Model Exhibits Motor Deficits and Neurodegenerative Characteristics of Amyotrophic Lateral Sclerosis}},
url = {{http://dx.doi.org/10.3390/cells15050420}},
doi = {{10.3390/cells15050420}},
volume = {{15}},
year = {{2026}},
}