Pathological levels of α-synuclein increase basal mitophagy in Parkinson's dopamine neurons

Pathogenic α-synuclein in iPSC-derived dopamine neurons from SNCA-Trp triplication increases basal mitophagy, linked to mitochondrial depletion and impaired neuronal firing.

• Why it matters: Elevated α-synuclein is linked to mitochondrial dysfunction, but how it dysregulates mitophagy and lipid-dependent mitochondrial dynamics in Parkinson’s dopamine neurons is unclear.
• What they did: iPSC-DANs carrying SNCA-Trp were compared with healthy controls using assays of basal mitophagy, mitochondrial mass, BNIP3/NIX accumulation, proteasome activity, single-cell RNAseq, lipid profiling, and DRP1 inhibition.
• The result: DRP1 inhibition reversed excessive basal mitophagy and restored cellular ATP and calcium release, and it rescued reduced neuronal firing activity in SNCA-Trp neurons.

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