title: Involvement of endoplasmic reticulum stress defined by activated unfolded protein response in multiple system atrophy.
abstract: Multiple system atrophy (MSA) and Parkinson's disease (PD) are classified as synucleinopathies that exhibit α-synuclein deposition in the central nervous system. Recently, activation of the unfolded protein response (UPR), which is a cellular stress response triggered by endoplasmic reticulum (ER) stress, was reported in PD and involvement of ER stress was indicated for this disease. To elucidate whether ER stress is also implicated in the pathology of MSA, we performed a series of immunohistochemical studies using MSA brain sections. Here, we showed the presence of an activated UPR response in oligodendroglia of postmortem MSA brains. The UPR protein-positive structures were observed in lesions where glial cytoplasmic inclusions (GCIs) appeared and colocalized highly in cells showing oligodendrocytic characteristics in the presence of α-synuclein inclusions. The UPR protein-positive structures appeared as granular shapes that are morphologically similar to granulovacuolar degeneration (GVD) and colocalized with GVD marker proteins. Double immunohistochemistry demonstrated that some of the activated UPR protein-positive structures were localized in oligodendrocytes that contained GCIs with faint α-synuclein labeling, without ubiquitination, and showing a strong correlation with the relocation of the tubulin polymerization-promoting protein (TPPP/p25α). These findings suggest that activation of the UPR may be induced at the early stage of the disease process, thus playing a pivotal role in the pathology of MSA.
authors.affiliation: Department of Neurology, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Kouki
authors.initials: K
authors.lastname: Makioka
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Yukio
authors.initials: Y
authors.lastname: Fujita
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Takatama
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakazato
authors.forename: Koichi
authors.initials: K
authors.lastname: Okamoto
mesh_terms: D000368:Aged; D001921:Brain / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D008297:Male; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009836:Oligodendroglia / Q000648:ultrastructure; D051899:Smad2 Protein / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology*; D051844:alpha-Synuclein / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D038362:Glycogen Synthase Kinase 3; D009419:Nerve Tissue Proteins; D051899:Smad2 Protein; D051844:alpha-Synuclein; D019892:eIF-2 Kinase; D016875:tau Proteins; C497782:SMAD2 protein, human