This collaborative work between Van Andel Institute, Michigan State University, and the VUGENE team sheds new light on the role of primary cilia in Parkinson’s Disease (PD).
Key insights from the study:
- Transcriptomic analysis of patients with PD revealed that primary cilia-related genes are upregulated at both early and late stages of the disease.
- Enhancing ciliogenesis via SHH signaling reduced αSyn pathology in vitro and protected dopamine neurons in vivo.
- Tet2 deletion boosts ciliogenesis and prevents αSyn propagation, offering a potential therapeutic pathway for PD.
By uncovering the link between Tet2, ciliogenesis, and αSyn pathology, our findings offer promising insights into new therapeutic pathways for PD.
Abstract
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.
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 Gordevičius (2025). Tet2 loss and enhanced ciliogenesis suppress α-synuclein pathology. Acta Neuropathologica Communications, vol 13 (1).
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Written by: Milda Milčiūtė
Cover image credits: Serhii / Adobe Stock
