Novikov_2025_J.Neurochem_169_e70204

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.