Huntington's disease (HD) and other polyglutamine (polyQ) neurodegenerative diseases are characterized by neuronal accumulation of the disease protein, suggesting that the cellular ability to handle abnormal proteins is compromised. As a multi-subunit protein localized in the mitochondria of eukaryotic cells, the F(0)F(1)-ATP synthase alpha belongs to the family of stress proteins HSP60. Currently, mounting evidences indicate F(0)F(1)-ATP synthase alpha may play a role in neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Recently, ATP synthase alpha was reported to have protective and therapeutic roles in primary cardiacmyocytes of iron-overloaded rats by lowering ROS production. However, little is understood about the role of ATP synthase alpha in cell death and neurodegeneration. Here, we demonstrate that overexpression of ATP synthase alpha suppresses huntingtin (htt) polyQ aggregation and toxicity in transfected SH-SY5Y cell lines. Overexpression of ATP synthase alpha is able to protect cell death caused by polyglutamine-expanded htt. Transient overexpression of ATP synthase alpha suppresses the aggregate formation by estimation of polyQ aggregation, Western blot analysis, and filter trap assay (FTA) in transfected SH-SY5Y cells. These results indicated that ATP synthase alpha has a strong inhibitory effect on polyglutamine aggregate formation and toxicity in vitro, and suggest a novel neuroprotective role of ATP synthase alpha.