Hyperphosphorylation and Insolubility of Alpha-synuclein in Transgenic Mouse Oligodendrocytes

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2002 May 30

PMID 12034752

Citations 152

Authors

Philipp J Kahle

Manuela Neumann

Laurence Ozmen

Veronika Muller

Helmut Jacobsen

Will Spooren

Babette Fuss

Barbara Mallon

Wendy B Macklin

Hideo Fujiwara

Masato Hasegawa

Takeshi Iwatsubo

Hans A Kretzschmar

Christian Haass

Affiliations

Soon will be listed here.

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.

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