Misfolded Proteinase K-resistant Hyperphosphorylated Alpha-synuclein in Aged Transgenic Mice with Locomotor Deterioration and in Human Alpha-synucleinopathies

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2002 Nov 20

PMID 12438441

Citations 174

Authors

Manuela Neumann

Philipp J Kahle

Benoit I Giasson

Laurence Ozmen

Edilio Borroni

Will Spooren

Veronika Muller

Sabine Odoy

Hideo Fujiwara

Masato Hasegawa

Takeshi Iwatsubo

John Q Trojanowski

Hans A Kretzschmar

Christian Haass

Affiliations

Soon will be listed here.

Abstract

The pathological modifications of alpha-synuclein (alphaS) in Parkinson disease and related diseases are poorly understood. We have detected misfolded alphaS in situ based on the proteinase K resistance (PK resistance) of alphaS fibrils, and using specific antibodies against S129-phosphorylated alphaS as well as oxidized alphaS. Unexpectedly massive neuritic pathology was found in affected human brain regions, in addition to classical alphaS pathology. PK resistance and abnormal phosphorylation of alphaS developed with increasing age in (Thy1)-h[A30P] alphaS transgenic mice, concomitant with formation of argyrophilic, thioflavin S-positive, and electron-dense inclusions that were occasionally ubiquitinated. alphaS pathology in the transgenic mice was predominantly in the brainstem and spinal cord. Astrogliosis was found in these heavily affected tissues. Homozygous mice showed the same pathology approximately one year earlier. The transgenic mice showed a progressive deterioration of locomotor function. Thus, misfolding and hyperphosphorylation of alphaS may cause dysfunction of affected brain regions.

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