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<p>Synucleinopathies, including Parkinson’s disease, involve α-synuclein (SNCA) accumulation and neurodegeneration, but early molecular effects of increased SNCA dosage remain incompletely defined. We examined human midbrain organoids derived from induced pluripotent stem cells carrying <i>SNCA</i> triplication and an isogenic control to assess early alterations in a 3D human model. We detected early changes in signalling linked to protein synthesis and stress responses prior to pronounced neurodegeneration. Proteomic and transcriptomic analyses indicated coordinated modulation of neuronal pathways and extracellular matrix components, including enrichment of perineuronal net–associated proteins alongside reduced expression of other matrix constituents. Ribosome profiling showed selective translational buffering for subsets of neuronal and matrix-related transcripts. Imaging revealed increased pericellular and interstitial matrix structures around neurons, emerging earlier in TH<sup>+</sup> cells. Collectively, these findings identify early, alterations in proteostasis-related signalling and extracellular matrix organization in human midbrain organoids with <i>SNCA</i> triplication, preceding overt neurodegenerative changes.</p>

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SNCA triplication disrupts proteostasis and extracellular architecture prior to neurodegeneration in human midbrain organoids

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月16日

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  • Elpida Statoulla,
  • Maria Zafeiri,
  • Kleanthi Chalkiadaki,
  • Georgia Voudouri,
  • Karmel S. Gkika,
  • Christos Papazoglou,
  • Thomas M. Durcan,
  • Arkady Khoutorsky,
  • Seyed Mehdi Jafarnejad,
  • Sarah Maguire,
  • Alexander Dityatev,
  • Christos G. Gkogkas

摘要

Synucleinopathies, including Parkinson’s disease, involve α-synuclein (SNCA) accumulation and neurodegeneration, but early molecular effects of increased SNCA dosage remain incompletely defined. We examined human midbrain organoids derived from induced pluripotent stem cells carrying SNCA triplication and an isogenic control to assess early alterations in a 3D human model. We detected early changes in signalling linked to protein synthesis and stress responses prior to pronounced neurodegeneration. Proteomic and transcriptomic analyses indicated coordinated modulation of neuronal pathways and extracellular matrix components, including enrichment of perineuronal net–associated proteins alongside reduced expression of other matrix constituents. Ribosome profiling showed selective translational buffering for subsets of neuronal and matrix-related transcripts. Imaging revealed increased pericellular and interstitial matrix structures around neurons, emerging earlier in TH+ cells. Collectively, these findings identify early, alterations in proteostasis-related signalling and extracellular matrix organization in human midbrain organoids with SNCA triplication, preceding overt neurodegenerative changes.