What question did this study set out to answer?

To investigate the pathogenic mechanisms of the Q789X mutation in DNAJC6 leading to PARK19 neurodegeneration.

March 14, 2026Open Access

PARK19 truncation mutant Dnajc6 causes lysosomal deficiency-induced upregulation of pathologic α-synuclein and neurodegeneration of substantia nigra dopaminergic cells in PARK19 knockin mice

Key Points

To investigate the pathogenic mechanisms of the Q789X mutation in DNAJC6 leading to PARK19 neurodegeneration.
Utilized Dnajc6Q787X/Q787X mice to study the effects of the mutation.
Assessed motor deficits and degeneration of dopaminergic neurons in the substantia nigra.
Evaluated lysosomal biogenesis and cathepsin D levels in relation to α-synuclein upregulation.
Mice showed motor deficits and loss of substantia nigra dopaminergic neurons.
Lysosomal deficiency resulted in decreased cathepsin D and increased α-synuclein oligomers.
Rapamycin treatment prevented α-synuclein upregulation and neurodegenerative phenotypes.

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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Cite This Study

Wang et al. (Thu,) studied this question.

synapsesocial.com/papers/69b4ba2718185d8a39802d71 https://doi.org/https://doi.org/10.1038/s41531-026-01317-8

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