Shane J F Cronin, Weonjin Yu, Ashley Hale, Simon Licht-Mayer, Mark J Crabtree, Joanna A Korecka, Evgenii O Tretiakov, Marco Sealey-Cardona, Mate Somlyay, Masahiro Onji, Meilin An, Jesse D Fox, Bruna Lenfers Turnes, Carlos Gomez-Diaz, Débora da Luz Scheffer, Domagoj Cikes, Vanja Nagy, Adelheid Weidinger, Alexandra Wolf, Harald Reither, Antoine Chabloz, Anoop Kavirayani, Shuan Rao, Nick Andrews, Alban Latremoliere, Michael Costigan, Gillian Douglas, Fernando Cini Freitas, Christian Pifl, Roger Walz, Robert Konrat, Don J Mahad, Andrey V Koslov, Alexandra Latini, Ole Isacson, Tibor Harkany, Penelope J Hallett, Stefan Bagby, Clifford J Woolf, Keith M Channon, Hyunsoo Shawn Je, Josef M Penninger
Dopa-responsive dystonia (DRD) and Parkinson's disease (PD) are movement disorders caused by the dysfunction of nigrostriatal dopaminergic neurons. Identifying druggable pathways and biomarkers for guiding therapies is crucial due to the debilitating nature of these disorders. Recent genetic studies have identified variants of GTP cyclohydrolase-1 (GCH1), the rate-limiting enzyme in tetrahydrobiopterin (BH4) synthesis, as causative for these movement disorders. Here, we show that genetic and pharmacological inhibition of BH4 synthesis in mice and human midbrain-like organoids accurately recapitulates motor, behavioral and biochemical characteristics of these human diseases, with severity of the phenotype correlating with extent of BH4 deficiency...
May 8, 2023: bioRxiv