Sephin1 reduces TDP-43 cytoplasmic mislocalization and improves motor neuron survival in ALS models.

ABSTRACT: A pathological hallmark of ALS is the abnormal accumulation of misfolded proteins (e.g., TDP-43) and enlarged endoplasmic reticulum (ER), indicating ER stress. To resolve this stress, cells initiate the Unfolded Protein Response (UPR). However, unresolved stress leads to apoptosis. In ALS, UPR activation fails to resolve proteostasis impairment. UPR activation modulators, among them Sephin1, reduce protein aggregates and improve motor neuron survival in ALS models. We demonstrate that following glutamate intoxication, Sephin1 increases motor neuron survival by reducing mitochondria ROS production and extranuclear TDP-43. Sephin1 reduces abnormal splicing because of TDP-43 nuclear loss of function following oxidative stress. In SOD1^G93A mice, Sephin1 treatment decreases TDP-43 in

SUBMITTER: Abgueguen E 

PROVIDER: S-EPMC12225689 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature