Objective/Rationale:
PARK18 is a genetic marker that was recently found to be associated with susceptibility to Parkinson’s disease (PD). The marker is encoded within the HLA-DRA gene, a gene that functions in immune responses. This proposal seeks to elucidate the mechanism by which PARK18 is associated with PD. We will examine the hypothesis that PARK18 resultsin exacerbated or diminished immune responses. Understanding this connection could potentially help design novel treatments.
Project Description:
To determine if the PARK18 genetic marker of PD is indicative of differential or misregulated HLA-DR gene expression (and subsequent changes in immune responses), immune cells isolated from the blood of PD patients and healthy volunteers will be compared. Immune cells from these individuals will be examined for expression of their HLA genes and a direct correlation between HLA-DR gene expression and disease will be made. Additionally, we will seek to determine if PARK18 is predictive of a novel gene regulatory element or mechanism by determining the genetic regulatory activity of the DNA surrounding PARK18 and examining ways in which this activity could be controlled, including an analysis of the epigenetic (non-DNA coding) patterns of inheritance associated with this region.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If the hypothesis that PARK18 is indicative of exacerbated immune responses to neuronal injury associated with PD, then distinct and novel diagnostic procedures will need to be developed to help predict onset, susceptibility, and prognosis to disease. Additionally, because this avenue has not been approached before, it could open up the door to new ways in treating the disease as an autoimmune disorder, as well as a neurological one.
Anticipated Outcome:
We hope to be able to define the role of PARK18 at the molecular level and understand why this marker is correlated with incidence of PD. As stated above, this understanding would provide a new direction to both diagnostics and treatment of PD and other neurodegenerative disorders.
Progress Report
PARK18 is a genetic marker that was recently linked to PD. PARK18 is found in a non-protein coding region of the HLA-DRA gene, a key immune response gene. Because the HLA-DRA protein is invariant between individuals, we hypothesized that this genetic linkage to PD concerned the regulation of either HLA-DRA or other HLA genes (HLA-DQ) within the locus. To begin to test this hypothesis, we sought to determine if there were differences in the expression of these key immune response genes in patients with PD compared to healthy age-matched control volunteers. We have analyzed 19 PD patients who possess the PD marker and 8 healthy age-matched controls who do not possess the marker. While our data analysis is preliminary, we found an unexpected difference in the level of expression of HLA genes within the locus and a discordance of expression between the HLA-DR and HLA-DQ genes within the locus. This discordance of expression may suggest that a different repertoire of self-antigens may be presented to the immune system in PD patients. This could have the net effect of increasing autoimmune or inflammatory responses to areas in the brain that are affected in patients with PD.
May 2012
Final Outcome
A single nucleotide polymorphism within the HLA-DRA gene locus was previously shown to be associated with PD. We analyzed peripheral blood from PD patients (n=51) homozygous for the high-risk allele (GG) or with the low-risk allele (AA), as well as age and sex-matched healthy controls (n=40) with low- or high-risk alleles. Consistent with the proposed hypothesis that the high-risk SNP is associated with a heightened immune response, we found that individuals with the GG allele have immune cells that either express higher basal levels of MHC-II (HLA-DR and DQ) and/or hyper-respond to an immune effector (interferon) that is often present during immune responses. These differences were evident in individuals without PD and may influence their PD risk after an environmental/pathogenic insult. Alternatively, these differences could influence autoimmune or inflammatory responses in areas of the brain that are affected in patients with PD. In support of this idea, we found that individuals with the high-risk allele and PD have the greatest MHC-II response to immune challenges and have higher UPDRS scores compared to PD patients with the low-risk allele.
December 2013
Presentations & Publications
Kannarkat GT, Cook DA, Chung J, Lee JK, Choi NM, Sperin EM, Factor S, Boss JM, and Tansey MG. 2013. The rs3129882 SNP Increases Susceptibility to Parkinson’s Disease through Modulation of Major Histocompatibility Complex II Gene Expression. In Preparation.
Kannarkat GT, Choi NM, Cook DA, Chung J, Lee JK, Factor S, Boss JM, and Tansey MG. 2013. PARK18 SNP is Associated with Differential Expression of Major Histocompatibilty Complex II Genes in Healthy Controls and Parkinson’s Disease Patients. World Parkinson’s Congress 2013. 1109.00.
Kannarkat GT, Choi NM, Chung J, Lee JK, Cook DA, Factor S, Boss JM, and Tansey MG. 2013. The PARK18 SNP is Associated with Altered Expression and Regulation of Major Histocompatibility Complex II Genes in Parkinson’s Disease Patients. Proceedings of the the 11th International Conference on Alzheimer’s and Parkinson’s Disease (AD/PD 2013). A-495-0002-00146.
Kannarkat GT, Choi NM, Lee JK, Cook DA, Boss JM, and Tansey MG. 2012. The PARK18 SNP is Associated with Altered Expression and Regulation of Major Histocompatibility Complex II Genes in Parkinson’s Disease Patients. Proceedings of the XI International Congress of Neuroimmunology (ISNI). J Neuroimmuno. 2012. 79: 154.
Kannarkat GT, Choi NM, Lee JK, Boss JM, and Tansey MG. 2012. The PARK18 SNP is Associated with Altered Expression and Regulation of Major Histocompatibility Complex II Genes in Parkinson’s Disease Patients. Society for Neuroscience. Program No 754.12. 2012 Neuroscience Meeting Planner. New Orleans, LA: Society for Neuroscience, 2012. Online.