BimEL as a possible molecular link between proteasome dysfunction and cell death induced by mutant huntingtin

Huntington’s disease (HD) is a devastating neurodegenerative disorder caused by an expanded polyglutamine repeat within the N‐terminus of the huntingtin protein. It is characterized by a selective loss of medium spiny neurons in the striatum. It has been suggested that impaired proteasome function and endoplasmic reticulum (ER) stress play important roles in mutant huntingtin (mHtt)‐induced cell death. However, the molecular link involved is poorly understood. In the present study, we identified the essential role of the extra long form of Bim (Bcl‐2 interacting mediator of cell death), BimEL, in mHtt‐induced cell death. BimEL protein expression level was significantly increased in cell lines expressing the N‐terminus of mHtt and in a mouse model of HD. Although quantitative RT‐PCR analysis indicated that BimEL mRNA was increased in cells expressing mHtt, we provided evidence showing that, at the post‐translational level, phosphorylation of BimEL played a more important role in regulating BimEL expression. Up‐regulation of BimEL facilitated the translocation of Bax to the mitochondrial membrane, which further led to cytochrome c release and cell death. On the other hand, knocking down BimEL expression prevented mHtt‐induced cell death. Taken together, these findings suggest that BimEL is a key element in regulating mHtt‐induced cell death. A model depicting the role of BimEL in linking mHtt‐induced ER stress and proteasome dysfunction to cell death is proposed.