title: Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleinopathies.
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.
authors.affiliation: Department of Neuropathology, Ludwig Maximilians University, Munich, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Neumann
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Kahle
authors.forename: Benoit I
authors.initials: BI
authors.lastname: Giasson
authors.forename: Laurence
authors.initials: L
authors.lastname: Ozmen
authors.forename: Edilio
authors.initials: E
authors.lastname: Borroni
authors.forename: Will
authors.initials: W
authors.lastname: Spooren
authors.forename: Veronika
authors.initials: V
authors.lastname: Müller
authors.forename: Sabine
authors.initials: S
authors.lastname: Odoy
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: John Q
authors.initials: JQ
authors.lastname: Trojanowski
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 / Q000473:pathology; D004351:Drug Resistance; D019286:Endopeptidase K / Q000378:metabolism*; D005260:Female; D018628:Gene Dosage; D006801:Humans; D066298:In Vitro Techniques; D020961:Lewy Body Disease / Q000378:metabolism / Q000473:pathology; D008124:Locomotion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D017510:Protein Folding; D051843:Synucleins; D051844:alpha-Synuclein
chemical_list: D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D019286:Endopeptidase K