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

Research output: Contribution to journalJournal articlepeer-review

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.

Original languageEnglish
JournalJournal of Huntington's disease
Issue number2
Pages (from-to)121-140
Publication statusPublished - 2022

Bibliographical note

Funding Information:
We thank Rabab Nima for technical assistance, Jonas Treebak for donation of SOD2 antibodies and Asli Silahtaroglu for assistances and use of microscope. This work was supported by Arvid Nilssons Fond, Grosserer Valdemar Foersom & Hustru Thyra Foersom, født Ottos Fond, Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis’ Legat, and Frode V. Nyegaard og Hustrus Fond.

Publisher Copyright:
© 2022-IOS Press. All rights reserved.

    Research areas

  • Cortex, Huntington's disease, Mitochondria, Oxygen consumption, Striatum, Synapses, Synaptosomes

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