title: Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes.
abstract: (Oligodendro)glial cytoplasmic inclusions composed of alpha-synuclein (alpha SYN) characterize multiple system atrophy (MSA). Mature oligodendrocytes (OLs) do not normally express alpha SYN, so MSA pathology may arise from aberrant expression of alpha SYN in OLs. To study pathological deposition of alpha SYN in OLs, transgenic mice were generated in which human wild-type alpha SYN was driven by a proteolipid protein promoter. Transgenic alpha SYN was detected in OLs but no other brain cell type. At the light microscopic level, the transgenic alpha SYN profiles resembled glial cytoplasmic inclusions. Strikingly, the diagnostic hyperphosphorylation at S129 of alpha SYN was reproduced in the transgenic mice. A significant proportion of the transgenic alpha SYN was detergent insoluble, as in MSA patients. The histological and biochemical abnormalities were specific for the disease-relevant alpha SYN because control green fluorescent protein was fully soluble and evenly distributed throughout OL cell bodies and processes. Thus, ectopic expression alpha SYN in OLs might initiate salient features of MSA pathology.
authors.affiliation: Laboratory for Alzheimer's and Parkinson's Disease Research, Department of Biochemistry, Ludwig Maximilians University, D-80336 Munich, Germany. chaass@pbm.med.uni-muenchen.de
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Kahle
authors.forename: Manuela
authors.initials: M
authors.lastname: Neumann
authors.forename: Laurence
authors.initials: L
authors.lastname: Ozmen
authors.forename: Veronika
authors.initials: V
authors.lastname: Muller
authors.forename: Helmut
authors.initials: H
authors.lastname: Jacobsen
authors.forename: Will
authors.initials: W
authors.lastname: Spooren
authors.forename: Babette
authors.initials: B
authors.lastname: Fuss
authors.forename: Barbara
authors.initials: B
authors.lastname: Mallon
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Macklin
authors.forename: Hideo
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kretzschmar
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D019578:Multiple System Atrophy / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism*; D010766:Phosphorylation; D012995:Solubility; D051843:Synucleins; D051844:alpha-Synuclein
chemical_list: D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein