Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the deterioration of upper and lower motor neurons in the brain, brain stem, and spinal cord. Multiple missense mutations have been connected to familial ALS, including those in the Matrin-3 protein. Matrin-3 is an RNA and DNA-binding protein encoded by the MATR3 gene. Normally found in the nuclear matrix, Matrin-3 plays several roles vital to RNA metabolism, including splicing, RNA degradation, mRNA transport, mRNA stability, and transcription. Mutations in MATR3 leading to familial ALS include P154S and S85C, but the mechanisms through which these mutations contribute to ALS pathology remain unknown. This makes mouse models particularly useful in elucidating pathology mechanisms, ultimately having the potential to serve as preclinical models for therapeutic drugs. Because of the importance of animal models, we worked to create ALS mouse models for the MATR3 P154S and S85C mutations. We specifically generated two CRISPR/Cas9 mediated knock-in mouse models containing the MATR3 P154S or S85C mutation expressed under the control of the endogenous promoter. Both the homozygous and heterozygous P154S mice developed no physical or motor defects or shortening of lifespan compared to the wildtype mice. They also exhibited no ALS-like pathology in either the muscle or spinal cord up to 24 months. In contrast, the homozygous S85C mice exhibited significant physical and motor differences, including smaller weight, impaired gait, and shortening of lifespan. Some ALS-like pathology was observed in the muscle, but pathology remained limited in the spinal cord of the homozygous mice up to 12 months. In conclusion, our data suggests that the MATR3 P154S mutation alone does not cause ALS in vivo, while the MATR3 S85C mutation induces significant motor deficits, with pathology in the spinal cord potentially beginning at older ages not examined in our study.

Traumatic brain injury (TBI) is defined as an injury to the head that disrupts normal brain function. TBI has been described as a disease process that can lead to an increased risk for developing chronic neurodegenerative diseases, like frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). A pathological hallmark of FTLD and a hallmark of ALS is the nuclear mislocalization of TAR DNA Binding Protein 43 (TDP-43). This project aims to explore neurodegenerative effects of TBI on cortical lesion area using immunohistochemical markers of TDP-43 proteinopathies. We analyzed the total percent of NEUN positive cells displaying TDP-43 nuclear mislocalization. We found that the percent of NEUN positive cells displaying TDP-43 nuclear mislocalization was significantly higher in cortical tissue following TBI when compared to the age-matched control brains. The cortical lesion area was analyzed for each injured brain sample, with respect to days post-injury (DPI), and it was found that there were no statistically significant differences between cortical lesion areas across time points. The percent of NEUN positive cells displaying TDP-43 nuclear mislocalization was analyzed for each cortical tissue sample, with respect to cortical lesion area, and it was found that there were no statistically significant differences between the percent of NEUN positive cells displaying TDP-43 nuclear mislocalization, with respect to cortical lesion area. In conclusion, we found no correlation between the percent of cortical NEUN positive cells displaying TDP-43 nuclear mislocalization with respect to the size of the cortical lesion area.