Deng Isaac Bul, Follett Jordan, Fox Jesse D, Wall Shannon, Farrer Matthew J
Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
NPJ Parkinsons Dis. 2025 May 30;11(1):143. doi: 10.1038/s41531-025-00991-4.
Bi-allelic autosomal recessive pathogenic variants in DNAJC12 lead to a constellation of neurological features, including young-onset Parkinson's disease. DNAJC12 is a co-chaperone for enzymes involved in biogenic amines synthesis. In vitro, we discovered overexpressed DNAJC12 forms a complex with guanine triphosphate cyclohydrolase 1 (GCH1), a rate-limiting enzyme in the synthesis of tetrahydrobiopterin, a cofactor for biogenic amine synthesis. We also confirm DNAJC12's interaction with tyrosine (TH) and tryptophan hydroxylases, paramount for dopamine (DA) and serotonin (5-HT) synthesis. In-vitro knock-down of DNAJC12 with a siRNA destabilizes DNAJC12-TH-GCH1 complex, whereas reciprocal co-overexpression of TH and GCH1 increases endogenous DNAJC12. Dnajc12 knock-out mice (DKO) exhibit reduced exploratory behavior at 3 months of age in open-field testing. In striatal tissue, total DA and 5-HT, and electrically evoked DA release are all reduced, with enhanced phosphorylation of Th at Ser31 and Ser40. DKO mice present models to develop/refine therapeutics approaches for biogenic amines disorders.
DNAJC12基因的双等位基因常染色体隐性致病变异会导致一系列神经学特征，包括早发性帕金森病。DNAJC12是参与生物胺合成的酶的共伴侣蛋白。在体外，我们发现过表达的DNAJC12与鸟苷三磷酸环化水解酶1（GCH1）形成复合物，GCH1是生物胺合成辅因子四氢生物蝶呤合成中的限速酶。我们还证实了DNAJC12与酪氨酸羟化酶（TH）和色氨酸羟化酶的相互作用，这对多巴胺（DA）和5-羟色胺（5-HT）的合成至关重要。用小干扰RNA（siRNA）在体外敲低DNAJC12会破坏DNAJC12-TH-GCH1复合物的稳定性，而TH和GCH1的相互共过表达会增加内源性DNAJC12。Dnajc12基因敲除小鼠（DKO）在3个月大时进行旷场试验时表现出探索行为减少。在纹状体组织中，总DA和5-HT以及电诱发的DA释放均减少，Th在Ser31和Ser40处的磷酸化增强。DKO小鼠为开发/完善生物胺紊乱的治疗方法提供了模型。
