A Longitudinal Study of Sex Differences in a TDP‐43 Mouse Model Reveals STI1 Regulation of TDP‐43 Proteinopathy and Motor Deficits

Amyotrophic lateral sclerosis (ALS) is a disease influenced by a complex interplay of age, genetics, and sex. Most ALS cases are sporadic, and individuals with this disease show elevated levels of TDP‐43 in their central nervous system and aggregated cytoplasmic inclusions containing TDP‐43 in neurons. Misfolded and aggregated proteins like TDP‐43 can be refolded or marked for degradation by molecular chaperones and their co‐chaperone partners. In this study, we use a mouse model of ALS that mildly overexpresses human wild‐type TDP‐43 in neurons to explore how aging affects the onset of motor abnormalities and proteinopathy in male and female mice. We found that the age‐dependent onset of motor symptoms is more pronounced in male mice, despite both sexes sharing similar TDP‐43 pathology. Further, we found that reducing the activity of STI1, an Hsp90 co‐chaperone, was associated with reduced mislocalized TDP‐43 in the brain and spinal cord and partially rescued some motor deficits. By contrast, overexpressing STI1 seemed to be deleterious, exacerbating the levels of C‐terminal TDP‐43 fragments in the cytoplasm, worsening motor abnormalities and reducing lifespan. Our findings reveal that sex is a key biological factor in an ALS mouse model of TDP‐43 overexpression and provide novel insights on the role of STI1 and proteostasis in mediating TDP‐43 pathology.