Kunwar Jung-KC

Abstract Pathogenic variants of the J-domain protein DNAJC12 cause parkinsonism, which is associated with a defective interaction of DNAJC12 with tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis. In this work, we characterize the formation of the TH:DNAJC12 complex, showing that DNAJC12 binding stabilizes both TH and the variant TH-p.R202H, associated with TH deficiency.

Tyrosine hydroxylase (TH) catalyzes the conversion of l-tyrosine into l-DOPA, which is the rate-limiting step in the synthesis of catecholamines, such as dopamine, in dopaminergergic neurons. Low dopamine levels and death of the dopaminergic neurons are hallmarks of Parkinson's disease (PD), where ?-synuclein is also a key player. TH is highly regulated, notably by phosphorylation of several Ser/Thr residues in the N-terminal tail.