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Allelic difference in Mhc2ta confers altered microglial activation and susceptibility to α-synuclein-induced dopaminergic neurodegeneration

Jimenez, Itzia LU ; Jewett, Michael LU ; Tontanahal, Ashmita LU ; Romero-Ramos, Marina LU and Swanberg, Maria LU (2017) In Neurobiology of Disease 106. p.279-290
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... (More)

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.

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publication status
published
subject
keywords
Alpha synuclein, Dopaminergic neurons, Genetics, Inflammation, Mhc2ta, MHCII, Microglia, Neurodegeneration, Parkinson's disease
in
Neurobiology of Disease
volume
106
pages
12 pages
publisher
Elsevier
external identifiers
  • scopus:85026215585
  • wos:000408290800025
ISSN
0969-9961
DOI
10.1016/j.nbd.2017.07.016
language
English
LU publication?
yes
id
c2770412-b41d-4cff-98fa-a85f4d13e134
date added to LUP
2017-08-04 09:52:22
date last changed
2018-04-29 04:41:23
@article{c2770412-b41d-4cff-98fa-a85f4d13e134,
  abstract     = {<p>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.</p>},
  author       = {Jimenez, Itzia and Jewett, Michael and Tontanahal, Ashmita and Romero-Ramos, Marina and Swanberg, Maria},
  issn         = {0969-9961},
  keyword      = {Alpha synuclein,Dopaminergic neurons,Genetics,Inflammation,Mhc2ta,MHCII,Microglia,Neurodegeneration,Parkinson's disease},
  language     = {eng},
  month        = {10},
  pages        = {279--290},
  publisher    = {Elsevier},
  series       = {Neurobiology of Disease},
  title        = {Allelic difference in Mhc2ta confers altered microglial activation and susceptibility to α-synuclein-induced dopaminergic neurodegeneration},
  url          = {http://dx.doi.org/10.1016/j.nbd.2017.07.016},
  volume       = {106},
  year         = {2017},
}