Abstract
Homozygous (Q789X) DNAJC6 mutation causes PARK19. Q787 of Dnajc6 corresponds to Q789 of DNAJC6. Dnajc6Q787X/Q787X mouse was utilized to elucidate pathomechanisms underlying (Q789X) DNAJC6-induced PARK19. Dnajc6Q787X/Q787X mice displayed PARK19 motor deficits and degeneration of substantia nigra (SN) dopaminergic neurons. (Q787X) Dnajc6 decreased clathrin heavy chain and lysosomal number, leading to downregulation of lysosomal cathepsin D and upregulation of α-synuclein or α-synuclein oligomers in SN dopaminergic neurons. Lysosomal biogenesis activator rapamycin precluded (Q787X) Dnajc6-induced downregulation of cathepsin D, upregulation of α-synuclein, and PARK19 phenotypes. (Q787X) Dnajc6-induced elevation of ER and mitochondrial α-synuclein excited ER stress and mitochondrial pro-apoptotic cascades. (Q787X) Dnajc6-evoked α-synuclein oligomer overexpression activated SN microglia and NLRP3 inflammasome and upregulated IL-1β, IL-18, and TNF-α, which stimulated MKK4-JNK -c-Jun/ATF-2 and RIPK1-RIPK3-MLKL death cascades. Our results suggest that PARK19 (Q789X) DNAJC6 mutation causes lysosomal deficiency and impairs cathepsin D-mediated degradation of α-synuclein, resulting in upregulated α-synuclein-induced neurodegeneration of SN dopaminergic cells.
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Acknowledgements
The authors thank the National Laboratory Animal Center (Tainan, Taiwan) for preparing Dnajc6Q787X/+ knockin mice. This study was supported by the National Science and Technology Council, Taiwan (NSTC 113- 2320-B-182-026-MY3 to H.-L.W. and NSTC 114-2314-B-038-061 to T.-H.Y.), Chang Gung Medical Foundation (CMRPD1M0142 to H.-L.W.), and the Healthy Aging Research Center, Chang Gung University (EMRPD1M0451 to H.-L.W.).
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Hung-Li Wang, Ying-Ling Chen, Yi-Hsin Weng, and Tu-Hsueh Yeh conceptualized the study and designed the experiments; Hung-Li Wang, Ying-Ling Chen, Tai-Ju Chiu, Ching-Chi Chiu, Shu-Yu Liu, and Allen Hon-Lun Li performed the experiments and analyzed the data; Hung-Li Wang, Ying-Ling Chen, Yi-Hsin Weng, and Tu-Hsueh Yeh wrote the manuscript.
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Wang, HL., Chen, YL., Chiu, TJ. et al. PARK19 truncation mutant Dnajc6 causes lysosomal deficiency-induced upregulation of pathologic α-synuclein and neurodegeneration of substantia nigra dopaminergic cells in PARK19 knockin mice. npj Parkinsons Dis. (2026). https://doi.org/10.1038/s41531-026-01317-8
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DOI: https://doi.org/10.1038/s41531-026-01317-8
