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Allelic difference in Mhc2ta confers altered microglial activation and susceptibility to α-synuclein-induced dopaminergic neurodegeneration.
Neurobiol Dis. 2017 Oct; 106:279-290.ND

Abstract

Parkinson's Disease (PD) is a complex and heterogeneous neurodegenerative disease characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta and pathological intracellular accumulation of alpha-synuclein (α-syn). In the vast majority of PD patients, the disease has a complex etiology, defined by multiple genetic and environmental risk factors. Common genetic variants in the human leukocyte-antigen (HLA) region have been associated to PD risk and the carriage of these can double the risk to develop PD. Among these common genetic variants are the ones that modulate the expression of MHCII genes. MHCII molecules encoded in the HLA-region are responsible for antigen presentation to the adaptive immune system and have a key role in inflammatory processes. In addition to cis‑variants affecting MHCII expression, a transactivator encoded by the Mhc2ta gene is the major regulator of MHCII expression. We have previously identified variations in the promoter region of Mhc2ta, encoded in the VRA4 region, to regulate MHCII expression in rats. The expression of MHCII is known to be required in the response to α-syn. However, how the expression of MHCII affects the activation of microglial or the impact of physiological, differential Mhc2ta expression on degeneration of dopaminergic neurons has not previously been addressed. Here we addressed the implications of common genetic allelic variants of the major regulator of MHCII expression on α-syn-induced microglia activation and the severity of the dopaminergic neurodegeneration. We used a viral vector technology to overexpress α-syn in two rat strains; Dark agouti (DA) wild type and DA.VRA4-congenic rats. The congenic strain carries PVG alleles in the VRA4 locus and therefore displays lower Mhc2ta expression levels compared to DA rats. We analyzed the impact of this physiological differential Mhc2ta expression on gliosis, inflammation, degeneration of the nigro-striatal dopamine system and behavioral deficits after α-syn overexpression. We report that allelic variants of Mhc2ta differently modified the microglial activation in response to overexpression of human α-syn in rats. Overexpression of α-syn led to a larger denervation of the nigro-striatal system and significant behavioral deficits in DA.VRA4 congenic rats with lower Mhc2ta expression compared to DA rats. These results indicate that Mhc2ta is a key upstream regulator of the inflammatory response in PD pathology.

Authors+Show Affiliations

Translational Neurogenetics Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.Translational Neurogenetics Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.Translational Neurogenetics Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.CNS Disease Modeling Group Department of Biomedicine, NEURODIN, Aarhus University, 8000 Aarhus, Denmark.Translational Neurogenetics Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden. Electronic address: maria.swanberg@med.lu.se.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28736195

Citation

Jimenez-Ferrer, Itzia, et al. "Allelic Difference in Mhc2ta Confers Altered Microglial Activation and Susceptibility to Α-synuclein-induced Dopaminergic Neurodegeneration." Neurobiology of Disease, vol. 106, 2017, pp. 279-290.
Jimenez-Ferrer I, Jewett M, Tontanahal A, et al. Allelic difference in Mhc2ta confers altered microglial activation and susceptibility to α-synuclein-induced dopaminergic neurodegeneration. Neurobiol Dis. 2017;106:279-290.
Jimenez-Ferrer, I., Jewett, M., Tontanahal, A., Romero-Ramos, M., & Swanberg, M. (2017). Allelic difference in Mhc2ta confers altered microglial activation and susceptibility to α-synuclein-induced dopaminergic neurodegeneration. Neurobiology of Disease, 106, 279-290. https://doi.org/10.1016/j.nbd.2017.07.016
Jimenez-Ferrer I, et al. Allelic Difference in Mhc2ta Confers Altered Microglial Activation and Susceptibility to Α-synuclein-induced Dopaminergic Neurodegeneration. Neurobiol Dis. 2017;106:279-290. PubMed PMID: 28736195.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Allelic difference in Mhc2ta confers altered microglial activation and susceptibility to α-synuclein-induced dopaminergic neurodegeneration. AU - Jimenez-Ferrer,Itzia, AU - Jewett,Michael, AU - Tontanahal,Ashmita, AU - Romero-Ramos,Marina, AU - Swanberg,Maria, Y1 - 2017/07/20/ PY - 2017/01/30/received PY - 2017/06/20/revised PY - 2017/07/19/accepted PY - 2017/7/25/pubmed PY - 2018/5/16/medline PY - 2017/7/25/entrez KW - Alpha synuclein KW - Dopaminergic neurons KW - Genetics KW - Inflammation KW - MHCII KW - Mhc2ta KW - Microglia KW - Neurodegeneration KW - Parkinson's disease SP - 279 EP - 290 JF - Neurobiology of disease JO - Neurobiol Dis VL - 106 N2 - Parkinson's Disease (PD) is a complex and heterogeneous neurodegenerative disease characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta and pathological intracellular accumulation of alpha-synuclein (α-syn). In the vast majority of PD patients, the disease has a complex etiology, defined by multiple genetic and environmental risk factors. Common genetic variants in the human leukocyte-antigen (HLA) region have been associated to PD risk and the carriage of these can double the risk to develop PD. Among these common genetic variants are the ones that modulate the expression of MHCII genes. MHCII molecules encoded in the HLA-region are responsible for antigen presentation to the adaptive immune system and have a key role in inflammatory processes. In addition to cis‑variants affecting MHCII expression, a transactivator encoded by the Mhc2ta gene is the major regulator of MHCII expression. We have previously identified variations in the promoter region of Mhc2ta, encoded in the VRA4 region, to regulate MHCII expression in rats. The expression of MHCII is known to be required in the response to α-syn. However, how the expression of MHCII affects the activation of microglial or the impact of physiological, differential Mhc2ta expression on degeneration of dopaminergic neurons has not previously been addressed. Here we addressed the implications of common genetic allelic variants of the major regulator of MHCII expression on α-syn-induced microglia activation and the severity of the dopaminergic neurodegeneration. We used a viral vector technology to overexpress α-syn in two rat strains; Dark agouti (DA) wild type and DA.VRA4-congenic rats. The congenic strain carries PVG alleles in the VRA4 locus and therefore displays lower Mhc2ta expression levels compared to DA rats. We analyzed the impact of this physiological differential Mhc2ta expression on gliosis, inflammation, degeneration of the nigro-striatal dopamine system and behavioral deficits after α-syn overexpression. We report that allelic variants of Mhc2ta differently modified the microglial activation in response to overexpression of human α-syn in rats. Overexpression of α-syn led to a larger denervation of the nigro-striatal system and significant behavioral deficits in DA.VRA4 congenic rats with lower Mhc2ta expression compared to DA rats. These results indicate that Mhc2ta is a key upstream regulator of the inflammatory response in PD pathology. SN - 1095-953X UR - https://www.unboundmedicine.com/medline/citation/28736195/Allelic_difference_in_Mhc2ta_confers_altered_microglial_activation_and_susceptibility_to_α_synuclein_induced_dopaminergic_neurodegeneration_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(17)30168-7 DB - PRIME DP - Unbound Medicine ER -