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

• Published in: Molecular neurobiology 2024-11, Vol.61 (11), p.9032-9042
• Main Authors: Hui, Sarah, George, Jimmy, Kapadia, Minesh, Chau, Hien, Bariring, Zahn, Earnshaw, Rebecca, Shafiq, Kashfia, Kalia, Lorraine V., Kalia, Suneil K.
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - metabolism; Animals; Autophagy; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell death; Cell Line, Tumor; Cell migration; Dopamine receptors; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Humans; Mitochondria; Mitochondria - metabolism; Mitophagy; Mitophagy - physiology; Movement disorders; Mutants; Mutation - genetics; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Neurobiology; Neurodegeneration; Neurodegenerative diseases; Neurology; Neurons - metabolism; Neurons - pathology; Neurosciences; Original; Original Article; Parkinson's disease; pH effects; Protein turnover; Quality control; Rats; Rats, Sprague-Dawley; Substantia nigra; Synuclein; Up-Regulation
• ISSN: 0893-7648; 1559-1182; 1559-1182
• DOI: 10.1007/s12035-024-04131-6

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.