Formation of seeding-competent α-synuclein aggregates in parkin-deficient iPSC-derived human neurons.

Loss-of-function mutations in PARK2 (parkin) cause early-onset familial Parkinson's disease (PD) and may also contribute to sporadic PD. While Lewy bodies, enriched in aggregated phosphorylated α-synuclein (α-Syn), are typical in PD, their presence in PARK2-mediated PD remains debated. Using human isogenic PARK2 induced pluripotent stem cell-derived neurons, we investigated α-Syn pathology under parkin deficiency. PARK2 neurons showed elevated intracellular aggregated and total α-Syn levels, increased α-Syn release, and higher levels of aggregation-inducing α-Syn seeds. These neurons also displayed more pSer129 α-Syn inclusions, which were further enhanced by α-Syn preformed fibril (PFF) exposure. Moreover, we identified synaptic loss in the PARK2 neurons, exacerbated by PFF treatment, and dysregulated Ca homeostasis consistent with enhanced activity of the smooth endoplasmic reticulum Ca-ATPase (SERCA). Our data provide an important contribution to the debate on the role of α-Syn in the pathology of PARK2-related PD and challenge the view of PARK2-related PD as a non-synucleinopathy.