CHARACTERIZATION OF PARKINSON’S DISEASE GENE DJ-1/PARK7 IN CD4+CD25+FOXP3+ REGULATORY T-CELLS

DJ-1, also known as PARK7, as its name suggests, is one of the familial Parkinson’s disease (PD) genes. Defects in human DJ-1 are the cause of autosomal recessive early-onset PD. DJ-1 is a redox-responsive protein and is long thought to mainly play an essential protective role in neurons. DJ-1 is ubiquitously expressed throughout the body rather than only in brain and is involved in several biological functions. We here seek to characterize a novel role of DJ-1 in regulatory T cells, currently recognized as CD4+CD25+FOXP3+ regulatory T-cells (Tregs), which are well-known immune suppressor cells in many peripheral diseases and emerging to play a role in several neurodegenerative diseases

PARK7/DJ-1 promotes pyruvate dehydrogenase activity and maintains T

Pyruvate dehydrogenase (PDH) is the gatekeeper enzyme of the tricarboxylic acid (TCA) cycle. Here we show that the deglycase DJ-1 (encoded by PARK7, a key familial Parkinson\u27s disease gene) is a pacemaker regulating PDH activity in CD

PARK7/DJ-1 promotes pyruvate dehydrogenase activity and maintains T(reg) homeostasis during ageing.

Pyruvate dehydrogenase (PDH) is the gatekeeper enzyme of the tricarboxylic acid (TCA) cycle. Here we show that the deglycase DJ-1 (encoded by PARK7, a key familial Parkinson's disease gene) is a pacemaker regulating PDH activity in CD4(+) regulatory T cells (T(reg) cells). DJ-1 binds to PDHE1-β (PDHB), inhibiting phosphorylation of PDHE1-α (PDHA), thus promoting PDH activity and oxidative phosphorylation (OXPHOS). Park7 (Dj-1) deletion impairs T(reg) survival starting in young mice and reduces T(reg) homeostatic proliferation and cellularity only in aged mice. This leads to increased severity in aged mice during the remission of experimental autoimmune encephalomyelitis (EAE). Dj-1 deletion also compromises differentiation of inducible T(reg) cells especially in aged mice, and the impairment occurs via regulation of PDHB. These findings provide unforeseen insight into the complicated regulatory machinery of the PDH complex. As T(reg) homeostasis is dysregulated in many complex diseases, the DJ-1-PDHB axis represents a potential target to maintain or re-establish T(reg) homeostasis