Central biogenic amine deficiency with concomitant exploratory behavioral deficits in Dnajc12 knock-out mice

Isaac Bul Deng; Jordan Follett; Jesse D Fox; Shannon Wall; Matthew J Farrer

doi:10.1038/s41531-025-00991-4

Central biogenic amine deficiency with concomitant exploratory behavioral deficits in Dnajc12 knock-out mice

NPJ Parkinsons Dis. 2025 May 30;11(1):143. doi: 10.1038/s41531-025-00991-4.

Authors

Isaac Bul Deng¹, Jordan Follett¹, Jesse D Fox², Shannon Wall¹, Matthew J Farrer³

Affiliations

¹ Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
² Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
³ Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL, USA. m.farrer@ufl.edu.

Abstract

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.

Abstract

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