Inhibition of apoptosis signal-regulating kinase 1 reduces endoplasmic reticulum stress and nuclear huntingtin fragments in a mouse model of Huntington disease.

Abstract

Huntington's disease (HD) is characterized clinically by chorea, psychiatric disturbances, and dementia, while it is characterized pathologically by neuronal inclusions as well as striatal and cortical neurodegeneration. The neurodegeneration arises from the loss of long projection neurons in the cortex and striatum. In this study, we investigated the role of apoptosis signal-regulating kinase 1 (Ask1) in the pathogenesis of HD. We analyzed the expression of Ask1 and huntingtin (htt) within the striatum and cortex and also examined the interaction of Ask1 with htt fragments in HD (R6/2) mice. Additionally, we inhibited Ask1 and analyzed the resulting changes in brain-derived neurotrophic factor (BDNF) expression, motor function, and striatal atrophy. Ask1 activity was blocked using an Ask1 antibody raised against the C-terminus of the Ask1 protein. The anti-Ask1 antibody was infused into the striatum of the HD mice for four weeks using a micro-osmotic pump. The levels of Ask1 protein and endoplasmic reticulum (ER) stress were increased in HD mice. Binding of inactivated Ask1 to htt fragments was more prevalent in the cytosol than the nucleus of cortical neurons. Binding of inactivated Ask1 to htt fragments prevented translocation of the htt fragments into the nucleus, resulting in an improvement in motor dysfunction and atrophy. In the normal state, active Ask1 may help htt fragments enter the nucleus, while inactivated Ask1 hinders this translocation by binding to but not releasing fragmented htt into the nucleus. We propose that Ask1 may interact with htt fragments and subsequently induce ER stress. BDNF depletion may be prevented by targeting Ask1; this would decrease ER stress and possibly ameliorate behavioral or anatomical abnormalities that accompany HD. Therefore, regulating the amounts and activity of the Ask1 protein is a novel strategy for treatment of HD.