Formation of seeding-competent α-synuclein aggregates in parkin-deficient iPSC-derived human neurons
Abstract 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. Usin...
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| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-06-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-025-01038-4 |
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| Summary: | Abstract 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 Ca2+ homeostasis consistent with enhanced activity of the smooth endoplasmic reticulum Ca2+-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. |
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| ISSN: | 2373-8057 |