Progressive Mitochondrial Dysfunction of Striatal Synapses in R6/2 Mouse Model of Huntington's Disease

Autor:	Maria Hvidberg Petersen, Cecilie Wennemoes Willert, Jens Velde Andersen, Mette Madsen, Helle Sønderby Waagepetersen, Niels Henning Skotte, Anne Nørremølle
Rok vydání:	2022
Předmět:	Cellular and Molecular Neuroscience Disease Models Animal Mice Huntington Disease Synapses Animals Mice Transgenic Neurology (clinical) Reactive Oxygen Species Corpus Striatum Mitochondria
Zdroj:	Journal of Huntington's disease. 11(2)
ISSN:	1879-6400
Popis:	Background: Huntington’s disease (HD) is a neurodegenerative disorder characterized by synaptic dysfunction and loss of white matter volume especially in the striatum of the basal ganglia and to a lesser extent in the cerebral cortex. Studies investigating heterogeneity between synaptic and non-synaptic mitochondria have revealed a pronounced vulnerability of synaptic mitochondria, which may lead to synaptic dysfunction and loss. Objective: As mitochondrial dysfunction is a hallmark of HD pathogenesis, we investigated synaptic mitochondrial function from striatum and cortex of the transgenic R6/2 mouse model of HD. Methods: We assessed mitochondrial volume, ROS production, and antioxidant levels as well as mitochondrial respiration at different pathological stages. Results: Our results reveal that striatal synaptic mitochondria are more severely affected by HD pathology than those of the cortex. Striatal synaptosomes of R6/2 mice displayed a reduction in mitochondrial mass coinciding with increased ROS production and antioxidants levels indicating prolonged oxidative stress. Furthermore, synaptosomal oxygen consumption rates were significantly increased during depolarizing conditions, which was accompanied by a marked increase in mitochondrial proton leak of the striatal synaptosomes, indicating synaptic mitochondrial stress. Conclusion: Overall, our study provides new insight into the gradual changes of synaptic mitochondrial function in HD and suggests compensatory mitochondrial actions to maintain energy production in the HD brain, thereby supporting that mitochondrial dysfunction do indeed play a central role in early disease progression of HD.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e63688c6101d57aac431866c6f9df378 https://pubmed.ncbi.nlm.nih.gov/35311711 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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