Abstract
The DJ-1 gene, a causative gene for familial Parkinson’s disease (PD), has been reported to have various functions, including transcriptional regulation, antioxidant response, and chaperone and protease functions; however, the molecular mechanism associated with the pathogenesis of PD remains elusive. To further explore the molecular function of DJ-1 in the pathogenesis of PD, we compared protein expression profiles in brain tissues from wild-type and DJ-1-deficient mice. Two-dimensional difference gel electrophoresis analysis and subsequent analysis using data mining methods revealed alterations in the expression of molecules associated with energy production. We demonstrated that DJ-1 deletion inhibited S-nitrosylation of endogenous Parkin as well as overexpressed Parkin in neuroblastoma cells and mouse brain tissues. Thus, we used genome editing to generate neuroblastoma cells with DJ-1 deletion or S-nitrosylated cysteine mutation in Parkin and demonstrated that these cells exhibited similar phenotypes characterized by enhancement of cell death under mitochondrial depolarization and dysfunction of mitochondria. Our data indicate that DJ-1 is required for the S-nitrosylation of Parkin, which positively affects mitochondrial function, and suggest that the denitrosylation of Parkin via DJ-1 inactivation might contribute to PD pathogenesis and act as a therapeutic target.
Highlights
The protein deglycase DJ-1 is encoded by the PARK7 gene in humans[1,2]
We revealed that DJ-1 deletion inhibits the S-nitrosylation of endogenous Parkin as well as overexpressed Parkin and that the S-nitrosylation of endogenous Parkin maintains mitochondrial function and protects cells from cell death due to mitochondrial depolarization
These findings indicate that the activity of Parkin is regulated by both S-nitrosylation and phosphorylation and that defects in either modification can cause autosomal recessive juvenile parkinsonism (ARJP) (Fig. 5a)
Summary
The protein deglycase DJ-1 is encoded by the PARK7 gene in humans[1,2]. The DJ-1 gene was originally identified as an oncogene that enhances the Ras/MAPK pathway and transforms fibroblastic cells[1] and was later identified as a causative gene for autosomal recessive juvenile parkinsonism (ARJP)[1,2]. In Drosophila, deletion of parkin and pink[1], which are causative genes for ARJP, causes morphological transformation and mitochondrial dysfunction in energy-demanding tissues including muscles and brain[4]. Overexpression of DJ-1 protects against mitochondrial dysfunction in cells transiently transfected with shRNA targeting PINK1 and rescues the vulnerability of dopaminergic neurons to an inhibitor of mitochondrial complex I in mice with PINK1 deletion[8]. These findings indicate that DJ-1 operates parallel to PINK1, but not Parkin, in a pathway to maintain mitochondrial function during exposure to stress. We used genome editing to generate neuroblastoma cells with DJ-1 deletion and an S-nitrosylated cysteine mutation in Parkin and showed that these two mutated cell lines showed similar mitochondrial functional phenotypes
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
