TY - JOUR
T1 - Short-term succinic acid treatment mitigates cerebellar mitochondrial OXPHOS dysfunction, neurodegeneration and ataxia in a Purkinje-specific spinocerebellar ataxia type 1 (SCA1) mouse model
AU - Ferro, Austin
AU - Carbone, Emily
AU - Zhang, Jenny
AU - Marzouk, Evan
AU - Villegas, Monica
AU - Siegel, Asher
AU - Nguyen, Donna
AU - Possidente, Thomas
AU - Hartman, Jessilyn
AU - Polley, Kailen
AU - Ingram, Melissa A
AU - Berry, Georgia
AU - Reynolds, Thomas H
AU - Possidente, Bernard
AU - Frederick, Kimberley
AU - Ives, Stephen
AU - Lagalwar, Sarita
PY - 2017
Y1 - 2017
N2 - Mitochondrial dysfunction plays a significant role in neurodegenerative disease including ataxias and other movement disorders, particularly those marked by progressive degeneration in the cerebellum. In this study, we investigate the role of mitochondrial oxidative phosphorylation (OXPHOS) deficits in cerebellar tissue of a Purkinje cell-driven spinocerebellar ataxia type 1 (SCA1) mouse. Using RNA sequencing transcriptomics, OXPHOS complex assembly analysis and oxygen consumption assays, we report that in the presence of mutant polyglutamine-expanded ataxin-1, SCA1 mice display deficits in cerebellar OXPHOS complex I (NADH-coenzyme Q oxidoreductase). Complex I genes are upregulated at the time of symptom onset and upregulation persists into late stage disease; yet, functional assembly of complex I macromolecules are diminished and oxygen respiration through complex I is reduced. Acute treatment of postsymptomatic SCA1 mice with succinic acid, a complex II (succinate dehydrogenase) electron donor to bypass complex I dysfunction, ameliorated cerebellar OXPHOS dysfunction, reduced cerebellar pathology and improved motor behavior. Thus, exploration of mitochondrial dysfunction and its role in neurodegenerative ataxias, and warrants further investigation.
AB - Mitochondrial dysfunction plays a significant role in neurodegenerative disease including ataxias and other movement disorders, particularly those marked by progressive degeneration in the cerebellum. In this study, we investigate the role of mitochondrial oxidative phosphorylation (OXPHOS) deficits in cerebellar tissue of a Purkinje cell-driven spinocerebellar ataxia type 1 (SCA1) mouse. Using RNA sequencing transcriptomics, OXPHOS complex assembly analysis and oxygen consumption assays, we report that in the presence of mutant polyglutamine-expanded ataxin-1, SCA1 mice display deficits in cerebellar OXPHOS complex I (NADH-coenzyme Q oxidoreductase). Complex I genes are upregulated at the time of symptom onset and upregulation persists into late stage disease; yet, functional assembly of complex I macromolecules are diminished and oxygen respiration through complex I is reduced. Acute treatment of postsymptomatic SCA1 mice with succinic acid, a complex II (succinate dehydrogenase) electron donor to bypass complex I dysfunction, ameliorated cerebellar OXPHOS dysfunction, reduced cerebellar pathology and improved motor behavior. Thus, exploration of mitochondrial dysfunction and its role in neurodegenerative ataxias, and warrants further investigation.
KW - Animals
KW - Cerebellum/metabolism
KW - Disease Models, Animal
KW - Mice
KW - Mice, Transgenic
KW - Mitochondria/metabolism
KW - Oxidative Phosphorylation
KW - Purkinje Cells/pathology
KW - Spinocerebellar Ataxias/metabolism
KW - Succinic Acid/administration & dosage
U2 - 10.1371/journal.pone.0188425
DO - 10.1371/journal.pone.0188425
M3 - Article
C2 - 29211771
SN - 1932-6203
VL - 12
SP - e0188425
JO - PloS one
JF - PloS one
IS - 12
ER -