Short-term succinic acid treatment mitigates cerebellar mitochondrial OXPHOS dysfunction, neurodegeneration and ataxia in a Purkinje-specific spinocerebellar ataxia type 1 (SCA1) mouse model

Abstract

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.

Hippocampal mitochondrial dysfunction and psychiatric-relevant behavioral deficits in spinocerebellar ataxia 1 mouse model

“…Table S28). To validate results of previous study pointing out the reduced complex I/maximal respiration ratio in the cerebellum of the SCA1 mice 23 , we performed the same analysis with negative results (P = 0.44).…”

“…In addition to hippocampal atrophy and the related behavioral deficits, we also identified corresponding mitochondrial dysfunction in the hippocampus (but not in the cerebellum) of the young SCA1 mice. Although mitochondrial dysfunction comprises one of a number of common pathological mechanisms shared by various neurodegenerative diseases 19 , it has been studied only rarely in spinocerebellar ataxias focusing exclusively on cerebellar tissue/cells [23][24][25] . The fact that we did not determine any mitochondrial dysfunction in the cerebellum contradicts the results of previous studies 23, 24 .…”

“…The results suggest that targeting the mitochondrial function provides a promising approach in terms of enhancing hippocampal-related functions in SCA1. Agents developed to improve certain mitochondrial functions have already been shown to improve cerebellar neuropathology in SCA1 mice 23,24 . Moreover, lithium, a drug that stimulates mitochondrial functions in various brain and mitochondrial diseases [63][64][65][66] , has been shown to improve learning and hippocampal neuropathology in SCA1 mice 12 .…”

Polyglutamine Repeats in Neurodegenerative Diseases

“…These results are inconsistent with major mitochondrial defects occurring in HD. Although not a feature of early disease in SCA1, studies in a mouse model demonstrated reduced mitochondrial transcripts and protein during the course of disease (111). In transgenic mouse models of SCA3, mitochondrial DNA depletion is seen in affected neuronal regions (112).…”

Progress and prospects of metabolic therapy in multiple sclerosis

“…Окисляясь сукцинатдегидрогеназой, янтарная кислота в дыхательной цепи обеспечивает быстрый ресинтез АТФ клетками [22] и более выраженно, чем другие субстраты цикла Кребса, повышает количество восстановленных митохондриальных никотинамиддинуклеотидов (НАД+) [23]. Введение янтарной кислоты при некоторых экспериментальных моделях нейродегенеративных заболеваний приводит к быстрому снижению митохондриальной дисфункции и уменьшению неврологического дефекта [24].…”