Mitophagy Upregulation Occurs Early in the Neurodegenerative Process Mediated by α-Synuclein.

Autor: Hui S; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada., George J; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada., Kapadia M; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada., Chau H; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada., Bariring Z; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada., Earnshaw R; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada., Shafiq K; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada., Kalia LV; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada.; Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada.; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada.; CRANIA, Toronto, ON, Canada., Kalia SK; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada. suneil.kalia@utoronto.ca.; Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada. suneil.kalia@utoronto.ca.; KITE, University Health Network, Toronto, ON, Canada. suneil.kalia@utoronto.ca.; CRANIA, Toronto, ON, Canada. suneil.kalia@utoronto.ca.
Jazyk: angličtina
Zdroj: Molecular neurobiology [Mol Neurobiol] 2024 Nov; Vol. 61 (11), pp. 9032-9042. Date of Electronic Publication: 2024 Apr 06.
DOI: 10.1007/s12035-024-04131-6
Abstrakt: Parkinson's disease (PD) is a progressive neurogenerative movement disorder characterized by dopaminergic cell death within the substantia nigra pars compacta (SNpc) due to the aggregation-prone protein α-synuclein. Accumulation of α-synuclein is implicated in mitochondrial dysfunction and disruption of the autophagic turnover of mitochondria, or mitophagy, which is an essential quality control mechanism proposed to preserve mitochondrial fidelity in response to aging and stress. Yet, the precise relationship between α-synuclein accumulation, mitochondrial autophagy, and dopaminergic cell loss remains unresolved. Here, we determine the kinetics of α-synuclein overexpression and mitophagy using the pH-sensitive fluorescent mito-QC reporter. We find that overexpression of mutant A53T α-synuclein in either human SH-SY5Y cells or rat primary cortical neurons induces mitophagy. Moreover, the accumulation of mutant A53T α-synuclein in the SNpc of rats results in mitophagy dysregulation that precedes the onset of dopaminergic neurodegeneration. This study reveals a role for mutant A53T α-synuclein in inducing mitochondrial dysfunction, which may be an early event contributing to neurodegeneration.
(© 2024. The Author(s).)
Databáze: MEDLINE
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