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<p>Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by CGG repeat expansions in the <i>FMR1</i> gene. While CGG repeat toxicity is established, the precise molecular mechanisms driving neurodegeneration remain unclear. Here, we show that a multi-omics strategy combined with TWAS reveals brain-region-specific molecular signatures and striking gene dysregulation in inhibitory neurons. Using conditional mouse models, we demonstrate that selective expression of expanded CGG repeats in GABAergic neurons is sufficient to recapitulate key pathologic hallmarks of FXTAS. We identify <i>PRKCG</i> as a genetic modifier of FXTAS, with cross-species evidence linking its overexpression to disease onset. Many dysregulated mRNAs in GABAergic neurons are targets of hnRNPA2/B1, an RNA-binding protein sequestered by CGG repeat RNA. Functional screening in <i>Drosophila</i> further establishes <i>PRKCG</i> as a potent modulator of CGG-associated neurotoxicity. These findings uncover a critical role of GABAergic neurons in FXTAS pathogenesis and position <i>PRKCG</i> as a promising therapeutic target.</p>

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Integrative transcriptome-wide association analyses reveal PRKCG-linked GABAergic dysfunction in Fragile X-associated tremor/ataxia syndrome

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月8日

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  • Yulin Jin,
  • Yiqu Cao,
  • Wenjing Ma,
  • Ronghua Li,
  • Yujing Li,
  • Yunhee Kang,
  • Jing Huang,
  • Michael P. Epstein,
  • Xiangxue Guo,
  • Junghwa Lim,
  • Natalia Rivera,
  • Ying Zhou,
  • Zhexing Wen,
  • Emily G. Allen,
  • Peng Jin

摘要

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by CGG repeat expansions in the FMR1 gene. While CGG repeat toxicity is established, the precise molecular mechanisms driving neurodegeneration remain unclear. Here, we show that a multi-omics strategy combined with TWAS reveals brain-region-specific molecular signatures and striking gene dysregulation in inhibitory neurons. Using conditional mouse models, we demonstrate that selective expression of expanded CGG repeats in GABAergic neurons is sufficient to recapitulate key pathologic hallmarks of FXTAS. We identify PRKCG as a genetic modifier of FXTAS, with cross-species evidence linking its overexpression to disease onset. Many dysregulated mRNAs in GABAergic neurons are targets of hnRNPA2/B1, an RNA-binding protein sequestered by CGG repeat RNA. Functional screening in Drosophila further establishes PRKCG as a potent modulator of CGG-associated neurotoxicity. These findings uncover a critical role of GABAergic neurons in FXTAS pathogenesis and position PRKCG as a promising therapeutic target.