DJ-1, a Parkinson’s Disease-associated Gene, Prevent Excessive Glial Inflammatory Responses through Interaction with SHP-1

Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder caused by the death of dopaminergic neurons in the substantia nigra. Importantly, altered astrocyte and microglial functions could contribute to neuronal death in PD. In this study, I demonstrate a novel mechanism by which DJ-1 (PARK7), an early onset autosomal recessive PD gene, negatively regulates inflammatory responses of astrocytes and microglia by facilitating the interaction between STAT1 and its phosphatase, SHP-1 (Src-homology 2-domain containing protein tyrosine phosphatase-1). Astrocytes and microglia cultured from DJ-1-knockout (KO) mice exhibited increased expression of inflammatory mediators and phosphorylation levels of STAT1 (p-STAT1) in response to interferon-gamma (IFN-g) compared to cells from wild-type (WT) mice. DJ-1 deficiency also attenuated IFN-g-induced interactions of SHP-1 with p-STAT1 and STAT1, measured 1 and 12 h after IFN-g treatment, respectively. Notably, DJ-1 bound to SHP-1 independently of IFN-g, whereas the interactions of DJ-1 with p-STAT1 and STAT1 were dependent on IFN-g. Similar results were obtained in brain slice cultures, where IFN-g induced much stronger STAT1 phosphorylation and inflammatory responses in KO slices than in WT slices. Moreover, IFN-g treatment induced neuronal damage in KO slices. Collectively, these findings suggest that DJ-1 may function as a scaffold protein that facilitates SHP-1 interactions with p-STAT1 and STAT1, thereby preventing extensive and prolonged STAT1 activation. Thus, the loss of DJ-1 function may increase the risk of PD by enhancing brain inflammation.

Author dc:creator

• 김, 종현

Contributors dc:contributor

• 조, 은혜
• 대학원 의생명과학과
• 200624311

• Parkinson's disease
• DJ-1
• SHP-1
• STAT1
• Brain inflammation
• 파킨슨병
• 뇌 염증반응

Language dc:language

en

Identifier

http://dcoll.ajou.ac.kr:9080/dcollection/jsp/common/DcLoOrgPer.jsp?sItemId=000000015977
000000015977

OAI identifier oai:identifier

oai:repository.ajou.ac.kr:201003/10858