Hyperphosphorylation and insolubility of alpha-synuclein in transgenic mouse oligodendrocytes.
(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.
Kahle
Philipp J
PJ
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
Neumann
Manuela
M
Ozmen
Laurence
L
Muller
Veronika
V
Jacobsen
Helmut
H
Spooren
Will
W
Fuss
Babette
B
Mallon
Barbara
B
Macklin
Wendy B
WB
Fujiwara
Hideo
H
Hasegawa
Masato
M
Iwatsubo
Takeshi
T
Kretzschmar
Hans A
HA
Haass
Christian
C
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
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein