THAP1 reguliert die Expression von alpha-Synuclein: Funktionelle Verknüpfung des Dystonie mit dem Parkinson Stoffwechselweg
Molekulare Biologie und Physiologie von Nerven- und Gliazellen
Zusammenfassung der Projektergebnisse
Evidence from patients with Parkinson's disease (PD) and our previously reported α-synuclein (SNCA) transgenic rat model support the idea that increased SNCA protein is a substantial risk factor of PD pathogenesis. However, little is known about the transcription control of the human SNCA gene in the brain in vivo. Using cellular and animal models for DYT6 dystonia, we observed that THAP1 regulates the expression of SNCA in human and rat neurons most likely through regulating the activities of SNCA intronic enhancers. Increased SNCA expression was observed in brain of SNCA/THAP1 double transgenic rats compared to SNCA single transgenic rats. These observations support that down-regulation or mutation of THAP1 would protect against synuclein accumulation in the dopaminergic neuron, while increased THAP1 expression will lead to increased SNCA expression and may stimulate more pronounced synuclein accumulation and thus aggregation in dopaminergic neuron. We further observed that deletion of the SNCA intronic enhancers reduces its expression drastically in the brain, which may provide new therapeutic approaches to prevent its accumulation and thus related neurodegenerative diseases defined as synucleinopathies.
Projektbezogene Publikationen (Auswahl)
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DYT6 mutated THAP1 is a cell type dependent regulator of the SP1 family. Brain, 145(11), 3968-3984.
Cheng, Fubo; Zheng, Wenxu; Barbuti, Peter Antony; Bonsi, Paola; Liu, Chang; Casadei, Nicolas; Ponterio, Giulia; Meringolo, Maria; Admard, Jakob; Dording, Claire Marie; Yu-Taeger, Libo; Nguyen, Huu Phuc; Grundmann-Hauser, Kathrin; Ott, Thomas; Houlden, Henry; Pisani, Antonio; Krüger, Rejko & Riess, Olaf
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Intronic enhancers of the human SNCA gene predominantly regulate its expression in brain in vivo. Science Advances, 8(47).
Cheng, Fubo; Zheng, Wenxu; Liu, Chang; Barbuti, Peter Antony; Yu-Taeger, Libo; Casadei, Nicolas; Huebener-Schmid, Jeannette; Admard, Jakob; Boldt, Karsten; Junger, Katrin; Ueffing, Marius; Houlden, Henry; Sharma, Manu; Kruger, Rejko; Grundmann-Hauser, Kathrin; Ott, Thomas & Riess, Olaf
