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<p>There are no approved treatments that slow Parkinson’s disease (PD) progression and therefore it is important to identify novel pathogenic mechanisms that can be targeted. Loss of the epigenetic marker, <i>Tet2</i> appears to have some beneficial effects in PD models, but the underlying mechanism of action is not well understood. We performed an unbiased transcriptomic analysis of cortical neurons isolated from patients with PD to identify dysregulated pathways and determine their potential contributions to the disease process. We discovered that genes associated with primary cilia, non-synaptic sensory and signaling organelles, are upregulated in both early and late stage PD patients. Enhancing ciliogenesis in primary cortical neurons via sonic hedgehog signaling suppressed the accumulation of α-synuclein pathology in vitro. Interestingly, deletion of <i>Tet2</i> in mice also enhanced the expression of primary cilia and sonic hedgehog signaling genes and reduced the accumulation of α-synuclein pathology and dopamine neuron degeneration in vivo. Our findings demonstrate the crucial role of TET2 loss in regulating ciliogenesis and potentially affecting the progression of PD pathology.</p>

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Tet2 loss and enhanced ciliogenesis suppress α-synuclein pathology

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月7日

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  • Emmanuel Quansah,
  • Naman Vatsa,
  • Elizabeth Ensink,
  • Jaycie Brown,
  • Tyce Cave,
  • Miguel Aguileta,
  • Emily Schulz,
  • Allison Lindquist,
  • Carla Gilliland,
  • Jennifer A. Steiner,
  • Martha L. Escobar Galvis,
  • Milda Milčiūtė,
  • Michael X. Henderson,
  • Patrik Brundin,
  • Lena Brundin,
  • Lee L. Marshall,
  • Juozas Gordevicius

摘要

There are no approved treatments that slow Parkinson’s disease (PD) progression and therefore it is important to identify novel pathogenic mechanisms that can be targeted. Loss of the epigenetic marker, Tet2 appears to have some beneficial effects in PD models, but the underlying mechanism of action is not well understood. We performed an unbiased transcriptomic analysis of cortical neurons isolated from patients with PD to identify dysregulated pathways and determine their potential contributions to the disease process. We discovered that genes associated with primary cilia, non-synaptic sensory and signaling organelles, are upregulated in both early and late stage PD patients. Enhancing ciliogenesis in primary cortical neurons via sonic hedgehog signaling suppressed the accumulation of α-synuclein pathology in vitro. Interestingly, deletion of Tet2 in mice also enhanced the expression of primary cilia and sonic hedgehog signaling genes and reduced the accumulation of α-synuclein pathology and dopamine neuron degeneration in vivo. Our findings demonstrate the crucial role of TET2 loss in regulating ciliogenesis and potentially affecting the progression of PD pathology.