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Background <p>The aggregation of α-Synuclein (αS) into amyloid fibrils and their deposition in intraneuronal Lewy bodies are hallmark features of Parkinson's disease (PD) and other synucleinopathies. Among the molecular players implicated in αS toxicity, the cellular prion protein (PrP<sup>C</sup>) has emerged as a potential modulator of αS-neuron interactions.</p> Results <p>Using confocal microscopy, colocalization analysis and both siRNA-induced PrP<sup>C</sup> silencing and antibody-based blockade, we investigated the contribution of PrP<sup>C</sup> to αS-induced neurotoxicity in human iPSC-derived dopaminergic neurons, primary rat cortical neurons and human SH-SY5Y neuroblastoma cells. We show that PrP<sup>C</sup> facilitated the early recruitment of αS prefibrillar type B* oligomers (OB*) and short fibrils (SF) to neuronal membranes, enhancing αS-induced Ca<sup>2+</sup> influx and membrane permeabilization. However, PrP<sup>C</sup> levels remained unchanged following prolonged exposure with OB* and SF, suggesting no feedback modulation of PrP<sup>C</sup> expression. While PrP<sup>C</sup> blockade partially inhibited the release of toxic soluble oligomers from αS fibrils, downstream cell death was only marginally reduced, indicating a limited contribution of PrP<sup>C</sup> to the final neurotoxic outcome. By contrast, extracellular Ca<sup>2+</sup> emerged as a major driver of αS toxicity, directly promoting the membrane recruitment, internalization and cytotoxic effects of αS aggregates.</p> Conclusions <p>Collectively, our findings indicate that while PrP<sup>C</sup> facilitates early events in αS aggregate interaction with neurons, the sustained neurotoxicity induced by αS prefibrillar oligomers and fibrils is predominantly mediated by extracellular Ca<sup>2+</sup>. This promotes aggregate-membrane interactions, membrane permeabilization, and intracellular Ca<sup>2+</sup> dyshomeostasis, thereby establishing a vicious cycle of neuronal dysfunction and death.</p>

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Cellular prion protein and calcium ions trigger the neurotoxicity of α-synuclein aggregates

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月9日

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  • Alessandra Bigi,
  • Andrea Carlotta Conti,
  • Liliana Napolitano,
  • Giuliana Fusco,
  • Alfonso De Simone,
  • Fabrizio Chiti,
  • Roberta Cascella,
  • Cristina Cecchi

摘要

Background

The aggregation of α-Synuclein (αS) into amyloid fibrils and their deposition in intraneuronal Lewy bodies are hallmark features of Parkinson's disease (PD) and other synucleinopathies. Among the molecular players implicated in αS toxicity, the cellular prion protein (PrPC) has emerged as a potential modulator of αS-neuron interactions.

Results

Using confocal microscopy, colocalization analysis and both siRNA-induced PrPC silencing and antibody-based blockade, we investigated the contribution of PrPC to αS-induced neurotoxicity in human iPSC-derived dopaminergic neurons, primary rat cortical neurons and human SH-SY5Y neuroblastoma cells. We show that PrPC facilitated the early recruitment of αS prefibrillar type B* oligomers (OB*) and short fibrils (SF) to neuronal membranes, enhancing αS-induced Ca2+ influx and membrane permeabilization. However, PrPC levels remained unchanged following prolonged exposure with OB* and SF, suggesting no feedback modulation of PrPC expression. While PrPC blockade partially inhibited the release of toxic soluble oligomers from αS fibrils, downstream cell death was only marginally reduced, indicating a limited contribution of PrPC to the final neurotoxic outcome. By contrast, extracellular Ca2+ emerged as a major driver of αS toxicity, directly promoting the membrane recruitment, internalization and cytotoxic effects of αS aggregates.

Conclusions

Collectively, our findings indicate that while PrPC facilitates early events in αS aggregate interaction with neurons, the sustained neurotoxicity induced by αS prefibrillar oligomers and fibrils is predominantly mediated by extracellular Ca2+. This promotes aggregate-membrane interactions, membrane permeabilization, and intracellular Ca2+ dyshomeostasis, thereby establishing a vicious cycle of neuronal dysfunction and death.