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<p>Loss-of-function mutations in <i>PARK2</i> (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 <i>PARK2</i>-mediated PD remains debated. Using human isogenic <i>PARK2</i><sup>−/−</sup> induced pluripotent stem cell-derived neurons, we investigated α-Syn pathology under parkin deficiency. <i>PARK2</i><sup>−/−</sup> 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<sup>+</sup> inclusions, which were further enhanced by α-Syn preformed fibril (PFF) exposure. Moreover, we identified synaptic loss in the <i>PARK2</i><sup><i>−/−</i></sup> neurons, exacerbated by PFF treatment, and dysregulated Ca<sup>2+</sup> homeostasis consistent with enhanced activity of the smooth endoplasmic reticulum Ca<sup>2+</sup>-ATPase (SERCA). Our data provide an important contribution to the debate on the role of α-Syn in the pathology of <i>PARK2</i>-related PD and challenge the view of <i>PARK2</i>-related PD as a non-synucleinopathy.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月21日

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  • Sissel Ida Schmidt,
  • Justyna Okarmus,
  • Daniel Aghaie Madsen,
  • Julie Schmidt Hansen,
  • Emil Gregersen,
  • Hjalte Gram,
  • Lucas S. Winkelmann,
  • Anderson Souza Oliveira,
  • Rachel Heon-Roberts,
  • Brent J. Ryan,
  • Kristine Freude,
  • Morten Blaabjerg,
  • Poul Henning Jensen,
  • Morten Meyer

摘要

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.