Journal Article

MHCII reduction is insufficient to protect mice from alpha-synuclein-induced degeneration and the Parkinson's HLA locus exhibits epigenetic regulation

Kline, Elizabeth M, Boss, Jeremy M, Menees, Kelly B, Wallings, Rebecca L, Maurer, Jeffrey, Tansey, Malú Gámez, Jernigan, Janna E, Joers, Valerie, Scharer, Christopher D, Hicks Sl, Sakeenah, Kelly, Sean D, Herrick M, Mary K, McFarland, Nikolaus R, Chang, Jianjun

2025

Overview

Major histocompatibility complex class II (MHCII) molecules are antigen presentation proteins and increased in post-mortem Parkinson's disease (PD) brain. Attempts to decrease MHCII expression have led to neuroprotection in PD mouse models. Our group reported that a SNP at in the MHCII gene Human leukocyte Antigen (HLA) DRA is associated with increased MHCII transcripts and surface protein and increased risk for late-onset idiopathic PD. We therefore hypothesized that decreased MHCII may mitigate dopaminergic degeneration. During an ongoing α-synuclein lesion, mice with MHCII reduction in systemic and brain innate immune cells (LysMCre+I-Ab or CRE+) displayed brain T cell repertoire shifts and greater preservation of the dopaminergic phenotype in nigrostriatal terminals. Next, we investigated a human cohort to characterize the immunophenotype of subjects with and without the high-risk genotype at the SNP. We confirmed that the high-risk genotype is associated with peripheral changes in MHCII inducibility, frequency of CD4+ T cells, and differentially accessible chromatin regions within the MHCII locus. Although our mouse studies indicate that myeloid MHCII reduction coinciding with an intact adaptive immune system is insufficient to fully protect dopamine neurons from α-synuclein-induced degeneration, our data are consistent with the overwhelming evidence implicating antigen presentation in PD pathophysiology.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Animal models / Antigen presentation / CD4 antigen / Chromatin / Dopamine receptors / Epigenetics / Flow cytometry / Gene deletion / Genotypes / Histocompatibility antigen HLA / Immune system / Lymphocytes T / Major histocompatibility complex / Movement disorders / Neurodegeneration / Neurodegenerative diseases / Neuroprotection / Parkinson's disease / Phenotypes / Single-nucleotide polymorphism / Synuclein