PARK7 Human
Description
Genetic and Molecular Profile of PARK7
Gene Characteristics
-
Symbol: PARK7
-
Protein: 189-amino acid protein with redox-sensitive chaperone activity
-
Conservation: Evolutionarily conserved across bacteria (E. coli YajL), fungi (S. pombe spDJ-1), and mammals .
Key Domains:
-
Catalytic cysteine residue (Cys-106 in humans) essential for enzymatic activity .
-
Pleiotropic roles: redox sensing, mitochondrial stabilization, and protein deglycation .
PARK7 in Parkinson’s Disease
Mechanism of Action:
PARK7 neutralizes reactive intermediates formed during glycolysis. Specifically, it degrades cyclic-1,3-phosphoglycerate, a reactive byproduct of 1,3-bisphosphoglycerate (1,3-BPG), preventing harmful modifications of proteins and metabolites .
Consequences of PARK7 Deficiency:
-
Accumulation of glycerate- and phosphoglycerate-modified proteins/metabolites in neurons .
-
Impaired mitochondrial function and increased oxidative stress, contributing to dopaminergic neuron loss .
Mutation Spectrum:
Epidemiology:
Recent Research Findings
Glycolytic Metabolite Detoxification (2022 Studies):
-
Mechanism: PARK7 degrades cyclic-1,3-phosphoglycerate, a reactive intermediate derived from 1,3-BPG, preventing non-enzymatic modifications of lysine residues on proteins (e.g., hemoglobin, glutamine synthetase) and metabolites (e.g., glutathione) .
-
Experimental Evidence:
Disease Links Beyond Parkinson’s:
-
Stargardt Macular Dystrophy: A patient with PARK7-associated PD also harbored a homozygous ABCA4 mutation due to uniparental disomy (UPD), highlighting PARK7’s pleiotropic genetic interactions .
-
Cancer: Overexpression reported in glioblastoma and lung adenocarcinoma, suggesting roles in redox homeostasis and tumor progression .
Clinical and Therapeutic Implications
Diagnostic Challenges:
-
PARK7-related PD often presents with atypical features (e.g., macular dystrophy, joint hypermobility), necessitating genomic sequencing for accurate diagnosis .
Therapeutic Targets:
-
Small-Molecule Activators: Compounds restoring PARK7’s enzymatic activity could mitigate metabolite-induced damage .
-
Gene Therapy: Viral vector-mediated PARK7 delivery rescued protein modifications in mouse models .
Unanswered Questions and Future Directions
-
Pathogenic Threshold: Why do PARK7 mutations take decades to cause PD despite continuous metabolite damage?
-
Interplay with Other Pathways: How do PARK7 interactions with glyoxalase systems influence disease progression?
-
Biomarker Potential: Can glycerate-modified proteins in cerebrospinal fluid serve as early PD markers?
Product Specs
Product Science Overview
PARK7 was initially identified as an oncogene product and later found to be associated with Parkinson’s disease (PD) and several types of cancer . The protein is approximately 20 kDa in size and is highly conserved across different species . Its primary function is to protect cells from stress conditions, particularly oxidative stress, through both enzymatic and non-enzymatic mechanisms .
The key element for PARK7’s function is the highly conserved cysteine residue at position 106 (Cys106) . This residue is crucial for the protein’s enzymatic glyoxalase activity and its non-enzymatic functions, including antioxidant, chaperone, co-transcription factor, and anti-apoptotic/ferroptotic activities . Oxidation of Cys106 is essential for PARK7 to perform these functions, but excessive oxidation can lead to the loss of its neuroprotective activity and contribute to the development of neurodegenerative diseases .
In the context of Parkinson’s disease, PARK7 is involved in protecting dopaminergic neurons from oxidative stress and other cellular stressors . The loss of function or mutations in the PARK7 gene can lead to the degeneration of these neurons, which is a hallmark of Parkinson’s disease . This makes PARK7 a critical target for therapeutic interventions aimed at slowing or preventing the progression of Parkinson’s disease .
Recent studies have focused on developing inhibitors, probes, and proteolysis-targeting chimeras (PROTACs) to study PARK7 in living cells . These tools help researchers understand the biological functions of PARK7 and its involvement in disease processes, opening new opportunities for therapeutic interventions .
