PARK7/DJ-1 in microglia: implications in Parkinson's disease and relevance as a therapeutic target

Abstract

Microglia are the immune effector cells of the brain playing critical roles in immune surveillance and neuroprotection in healthy conditions, while they can sustain neuroinflammatory and neurotoxic processes in neurodegenerative diseases, including Parkinson's disease (PD). Although the precise triggers of PD remain obscure, causative genetic mutations, which aid in the identification of molecular pathways underlying the pathogenesis of idiopathic forms, represent 10% of the patients. Among the inherited forms, loss of function of PARK7, which encodes the protein DJ-1, results in autosomal recessive early-onset PD. Yet, although protection against oxidative stress is the most prominent task ascribed to DJ-1, the underlying mechanisms linking DJ-1 deficiency to the onset of PD are a current matter of investigation. This review provides an overview of the role of DJ-1 in neuroinflammation, with a special focus on its functions in microglia genetic programs and immunological traits. Furthermore, it discusses the relevance of targeting dysregulated pathways in microglia under DJ-1 deficiency and their importance as therapeutic targets in PD. Lastly, it addresses the prospect to consider DJ-1, detected in its oxidized form in idiopathic PD, as a biomarker and to take into account DJ-1-enhancing compounds as therapeutics dampening oxidative stress and neuroinflammation.

Keywords: Microglia; NFκB; NLRP3/inflammasome; NRF2; Neurodegeneration; Neuroinflammation; Oxidative stress; PARK7/DJ-1; Parkinson’s disease.

Fig. 1

Functions of DJ-1. DJ-1 has a plethora of functions and was originally described as an oncogene A due to its involvement in cellular transformation and transcriptional regulation. B DJ-1 protects against oxidative stress both indirectly by stabilizing transcription factors inducing an antioxidant response or C directly by scavenging reactive oxygen species (ROS) both in the mitochondria and cytoplasm and indirectly by stabilizing transcription factors inducing an antioxidant response. The cysteine residue on position 106 (Cys106) within the DJ-1 protein acts as a sensor of redox state and can be oxidized to sulfinate (-SO₂⁻) and further to sulfonate (-SO₃⁻). Cys106-SO²⁻ has cytoprotective functions, whereas excessive oxidative stress can induce its overoxidation Cys106-SO₃⁻ and thereby its loss of function. Figure created with www.BioRender

Fig. 2

Functions of DJ-1 in microglia. A DJ-1 binds the p47 (green) unit of the NADPH oxidase preventing oxidative burst. B By preventing the binding of KEAP1 (yellow) to NRF2 (red), DJ-1 activates NRF2, which acts as a transcription factor regulating anti-oxidative responses. C DJ-1–NRF2 axis inhibits the inflammasome activation via TRX1. D DJ-1 facilitates the interaction of SHP-1 with STAT1, thereby inhibiting the STAT1 pathway. E DJ-1 binds the p65 subunit of the NFκB, thereby inhibiting the activation of the NFκB pathway. NRF2 NF-E2 related factor 2, KEAP 1 Kelch-like ECH protein 1, TRX1  Thioredoxin-1, SHP-1 Src-homology 2-domain containing protein tyrosine phosphatase-1, STAT-1 Signal transducer and activator of transcription 1, IKbα NF-κB inhibitor α, NFκB nuclear factor kappa light chain enhancer of B cells. Figure created with www.BioRender