A mitochondrial-targeted antioxidant (MitoQ) improves motor coordination and reduces Purkinje cell death in a mouse model of ARSACS

Márquez, Brenda Toscano; Leung, Tsz Chui Sophia; Hui, Jeanette; Charron, François; McKinney, R. Anne; Watt, Alanna J.

doi:10.1016/j.nbd.2023.106157

Cited by 6 publications

(5 citation statements)

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“…As in other neurodegenerative diseases, mitochondrial dysfunction is increasingly implicated in ARSACS pathology (18-20). For instance, MitoQ, a mitochondria-targeted antioxidant, was recently shown to improve motor coordination and delay Purkinje cell death in Sacs KO mice (21). In light of the present results, mitochondrial dysfunction in ARSACS is unlikely due to an imbalance of mitochondrial ssion and fusion, but rather a secondary consequence of improper folding and aggregation of one or more of the critical clients of the sacsin co-chaperone complex.…”

Section: Discussionsupporting

confidence: 47%

Driving Mitochondrial Fission Improves Cognitive, but not Motor Deficits in a Mouse Model of Ataxia of Charlevoix-Saguenay

Chen,

Merrill,

Jong

et al. 2024

Cerebellum

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Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by loss-of-function mutation in the SACS gene, which encodes sacsin, a putative HSP70-HSP90 co-chaperone. Previous studies with Sacs knock-out (KO) mice and patient-derived broblasts suggested that SACSIN mutations inhibit the function of the mitochondrial ssion enzyme dynamin-related protein 1 (Drp1). This in turn resulted in mitochondrial hyperfusion and dysfunction. We experimentally tested this hypothesis by genetically manipulating the mitochondrial ssion/fusion equilibrium, creating double KO (DKO) mice that also lack positive (PP2A/Bβ2) and negative (PKA/AKAP1) regulators of Drp1. Neither promoting mitochondrial fusion (Bβ2 KO) nor ssion (Akap1 KO) in uenced progression of motor symptoms in Sacs KO mice. However, our studies identi ed profound learning and memory de cits in aged Sacs KO mice. Moreover, this cognitive impairment was rescued in a gene dose-dependent manner by deletion of the Drp1 inhibitor PKA/Akap1. Our results are inconsistent with mitochondrial dysfunction as a primary pathogenic mechanism in ARSACS. Instead, they imply that promoting mitochondrial ssion may be bene cial at later stages of the disease when pathology extends to brain regions subserving learning and memory.

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Section: Discussionsupporting

confidence: 47%

Driving Mitochondrial Fission Improves Cognitive, but not Motor Deficits in a Mouse Model of Ataxia of Charlevoix-Saguenay

Chen,

Merrill,

Jong

et al. 2024

Cerebellum

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“…ROS accumulation is typically considered to be deleterious to cell health [ 74 ], and Purkinje cells have been shown to be particularly susceptible to oxidative stress [ 10 ]. Indeed, antioxidant treatments that reduce oxidative stress have been shown to prevent Purkinje cell death in mouse models of disease such as spinocerebellar ataxia type 1 (SCA1) and in Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) [ 43 , 62 ]. Given that we observed a reduction in Δψ m in the cerebellar vermis from SCA6 mice as disease progresses, we wondered if this would lead to excessive oxidative stress.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, our study suggests that by implementing therapeutic approaches to improve mitochondria health–for example, by inducing mitophagy or mitochondrial biogenesis [ 45 , 71 ] –we could improve cerebellar cell health and function. This could lead to improvement in the progression or severity of ataxia in SCA6 [ 43 ] in particular at late disease stages that are unlikely to be ameliorated by other therapeutic approaches that target mechanisms of disease onset.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial damage and impaired mitophagy contribute to disease progression in SCA6

Leung,

Fields,

Rana

et al. 2024

Acta Neuropathol

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Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease that manifests in midlife and progressively worsens with age. SCA6 is rare, and many patients are not diagnosed until long after disease onset. Whether disease-causing cellular alterations differ at different disease stages is currently unknown, but it is important to answer this question in order to identify appropriate therapeutic targets across disease duration. We used transcriptomics to identify changes in gene expression at disease onset in a well-established mouse model of SCA6 that recapitulates key disease features. We observed both up- and down-regulated genes with the major down-regulated gene ontology terms suggesting mitochondrial dysfunction. We explored mitochondrial function and structure and observed that changes in mitochondrial structure preceded changes in function, and that mitochondrial function was not significantly altered at disease onset but was impaired later during disease progression. We also detected elevated oxidative stress in cells at the same disease stage. In addition, we observed impairment in mitophagy that exacerbates mitochondrial dysfunction at late disease stages. In post-mortem SCA6 patient cerebellar tissue, we observed metabolic changes that are consistent with mitochondrial impairments, supporting our results from animal models being translatable to human disease. Our study reveals that mitochondrial dysfunction and impaired mitochondrial degradation likely contribute to disease progression in SCA6 and suggests that these could be promising targets for therapeutic interventions in particular for patients diagnosed after disease onset.

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“…Moreover, pre-and post-symptomatic in vivo MitoQ administration restores mitochondrial morphology and function and positively improves motor coordination and gait imbalance in an SCA1 mouse model, attenuating PN degeneration [19]. Recently, MitoQ chronic treatment in ARSACS mice displayed beneficial effects in PN survival and DCN innervation, preventing the motor decline associated with sacsin depletion [219].…”

Section: Pharmacological Treatments To Target Specific Pathomechanism...mentioning

confidence: 99%

Hereditary Ataxias: From Bench to Clinic, Where Do We Stand?

Pilotto,

Del Bondio,

Puccio

2024

Cells

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Cerebellar ataxias are a wide heterogeneous group of movement disorders. Within this broad umbrella of diseases, there are both genetics and sporadic forms. The clinical presentation of these conditions can exhibit a diverse range of symptoms across different age groups, spanning from pure cerebellar manifestations to sensory ataxia and multisystemic diseases. Over the last few decades, advancements in our understanding of genetics and molecular pathophysiology related to both dominant and recessive ataxias have propelled the field forward, paving the way for innovative therapeutic strategies aimed at preventing and arresting the progression of these diseases. Nevertheless, the rarity of certain forms of ataxia continues to pose challenges, leading to limited insights into the etiology of the disease and the identification of target pathways. Additionally, the lack of suitable models hampers efforts to comprehensively understand the molecular foundations of disease’s pathophysiology and test novel therapeutic interventions. In the following review, we describe the epidemiology, symptomatology, and pathological progression of hereditary ataxia, including both the prevalent and less common forms of these diseases. Furthermore, we illustrate the diverse molecular pathways and therapeutic approaches currently undergoing investigation in both pre-clinical studies and clinical trials. Finally, we address the existing and anticipated challenges within this field, encompassing both basic research and clinical endeavors.

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A mitochondrial-targeted antioxidant (MitoQ) improves motor coordination and reduces Purkinje cell death in a mouse model of ARSACS

Cited by 6 publications

References 50 publications

Driving Mitochondrial Fission Improves Cognitive, but not Motor Deficits in a Mouse Model of Ataxia of Charlevoix-Saguenay

Driving Mitochondrial Fission Improves Cognitive, but not Motor Deficits in a Mouse Model of Ataxia of Charlevoix-Saguenay

Mitochondrial damage and impaired mitophagy contribute to disease progression in SCA6

Hereditary Ataxias: From Bench to Clinic, Where Do We Stand?

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