Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration

Area of Science:

• Neuroscience
• Cell Biology
• Pathology

Background:

• Misfolded alpha-synuclein (αSyn) aggregates, forming Lewy bodies, are key pathological hallmarks of Parkinson's disease (PD).
• The precise mechanism by which αSyn contributes to PD pathogenesis remains unclear.
• Understanding αSyn's role is crucial for developing effective PD treatments.

Purpose of the Study:

• To investigate the subcellular localization of pathogenic αSyn aggregates in neurons.
• To determine the relationship between αSyn aggregation and mitochondrial function in neurodegenerative diseases.
• To identify potential therapeutic targets for α-synucleinopathies.

Main Methods:

• Utilized primary neuron cultures seeded with preformed αSyn amyloid fibrils (PFF).
• Assessed the binding of αSyn monomers and PFF to purified mitochondria in vitro.
• Confirmed findings in various αSyn aggregation models and postmortem brain tissues from PD patients.

Main Results:

• Pathogenic, serine 129 phosphorylated αSyn (ps-αSyn) predominantly binds to mitochondria, unlike physiological αSyn.
• Aggregated αSyn (PFF) shows preferential binding to mitochondria compared to αSyn monomers.
• Mitochondrial ps-αSyn accumulation correlates with impaired cellular respiration, indicating mitochondrial dysfunction.

Conclusions:

• Pathogenic αSyn aggregates selectively accumulate in mitochondria, leading to mitochondrial dysfunction.
• This mitochondrial dysfunction is a common downstream mechanism in α-synucleinopathies, including Parkinson's disease.
• Disrupting the interaction between ps-αSyn and mitochondria represents a promising therapeutic strategy for α-synucleinopathies.