Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ

作者：Stucki David M; Ruegsegger Celine; Steiner Silvio; Radecke Julika; Murphy Michael P; Zuber Benoit; Saxena Smita^*

来源：Free Radical Biology and Medicine, 2016, 97: 427-440.

DOI：10.1016/j.freeradbiomed.2016.07.005

• Spinocerebellar ataxia type 1
• Purkinje cells
• Mitochondria
• Oxidative stress
• Electron transport chain (ETC) activities
• Neurodegeneration
• Antioxidant MitoQ

Spinocerebellar ataxia type 1 (SCA1), due to an unstable polyglutamine expansion within the ubiquitously expressed Ataxin-1 protein, leads to the premature degeneration of Purkinje cells (PCs), decreasing motor coordination and causing death within 10-15 years of diagnosis. Currently, there are no therapies available to slow down disease progression. As secondary cellular impairments contributing to SCA1 progression are poorly understood, here, we focused on identifying those processes by performing a PC specific proteome profiling of Sca1(154Q/2Q). mice at a symptomatic stage. Mass spectrometry analysis revealed prominent alterations in mitochondrial proteins. Immunohistochemical and serial block-face scanning electron microscopy analyses confirmed that PCs underwent age-dependent alterations in mitochondrial morphology. Moreover, colorimetric assays demonstrated impairment of the electron transport chain complexes (ETC) and decrease in ATPase activity. Subsequently, we examined whether the mitochondria-targeted antioxidant MitoQ could restore mitochondrial dysfunction and prevent SCAT-associated pathology in Sca1(154Q/2Q). mice. MitoQ treatment both presymptomatically and when symptoms were evident ameliorated mitochondrial morphology and restored the activities of the ETC complexes. Notably, MitoQ slowed down the appearance of SCAT-linked neuropathology such as lack of motor coordination as well as prevented oxidative stress-induced DNA damage and PC loss. Our work identifies a central role for mitochondria in PC degeneration in SCAT and provides evidence for the supportive use of mitochondria-targeted therapeutics in slowing down disease progression.

• 出版日期2016-8