Common genetic variants in the MHCII transactivator regulate inflammation, α-syn pathology and dopaminergic cell loss

Identification: Jimenez Ferrer Carrillo, Itzia


Description

 

Common genetic variants in the MHCII transactivator regulate inflammation,  α-syn
pathology and dopaminergic cell loss  
 
Itzia Jimenez Ferrer Carrillo1, Antonio Boza-Serrano2, Kelvin C Luk3 , Virginia Lee3, Tomas Deierborg2, Maria Swanberg1
1Translational Neurogenetics Unit, Wallenberg Neuroscience Center, Lund University, Lund, Sweden; 2Experimental Neuroinflammation Laboratory, Lund University, Lund, Sweden; 3Deparment of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, 3600 Spruce Street, 3rd Fl Maloney Building, Philadelphia Pennsylvania 19104, USA
 
Inflammation is a key feature of Parkinson Disease (PD). In the postmortem, PD brains microglial activation and enhanced MHCII expression is seen concomitant to the accumulation of alpha-synuclein (α-syn) and loss of dopaminergic cells in the substantia nigra. It is known that single nucleotide polymorphism within the Human leukocyte locus (HLA) affecting the expression levels and/or binding specificity of MHCII molecules are associated with the risk of developing PD. It has also been shown that the inflammatory activation in PD is not confined to microglia in the brain but also involves the cells in the peripheral immune system, with an increased infiltration of immune cells into the brain parenchyma and an altered peripheral leukocyte profile in PD. The finding that α-syn epitopes can be recognized by T-lymphocytes further strengthens the notion that MHCII has a fundamental role in PD, linking innate and adaptive immune responses. However little is known if common genetic variants outside the HLA region are acting in trans to control the level of expression of MHCII and if this influences the susceptibility to PD. Therefore a clear understanding of how common genetic variants affecting MHCII expression participates in α-syn-pathology propagation and dopaminergic neurodegeneration in PD is highly needed.
To fill this gap, we have used a physiological relevant model of congenic rat strains (DA and DA.VRA4) which present differential MHCII expression levels due to an allelic variant in the major histocompatibility complex class two transactivator gene (Mhc2ta). We have previously shown that variants in the human orthologue, MHC2TA, are associated with inflammatory diseases. We hypothesize that common genetic variants of Mhc2ta affecting expression levels of MHCII exacerbate α-syn-pathology propagation and dopaminergic neurodegeneration in a α-syn seeding-propagation  PD model. Our results show that allelic variants in Mhc2ta, the major regulator of MHCII transcription, lead to a modified profile of microglial activation in response to overexpression of human α-syn in rats. The DA.VRA4 congenic rats, with the lower transcriptional activity of Mhc2ta and MHCII genes compared to DA rats, display enhanced denervation of the nigrostriatal system and a increased motor impairment. We also show the effect of differential Mhc2ta expression with regard to lymphocyte and cytokine profile, where the lower transcriptional activity of Mhc2ta induce a more proinflammatory profile in DA.VRA4 animals, as well as worsen the aggregation, propagation and toxicity of α-syn.
As existing therapies for PD patients merely treat the symptoms, extended knowledge of PD disease aetiology is needed to develop an effective therapy that can prevent, slow or stop the degenerative processes. Although upregulation of MHCII is a well-known characteristic of PD and the HLA-region is genetically associated with disease, the mechanisms behind these phenomena remain elusive. Our translational strategy combines the advantages of genetically and environmentally controlled experimental models with clinical studies, increasing the power elucidating Mhc2ta contribution to PD incidence and progression.
 

 

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