Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleinopathies.
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.
Neumann
Manuela
M
Department of Neuropathology, Ludwig Maximilians University, Munich, Germany.
Kahle
Philipp J
PJ
Giasson
Benoit I
BI
Ozmen
Laurence
L
Borroni
Edilio
E
Spooren
Will
W
Müller
Veronika
V
Odoy
Sabine
S
Fujiwara
Hideo
H
Hasegawa
Masato
M
Iwatsubo
Takeshi
T
Trojanowski
John Q
JQ
Kretzschmar
Hans A
HA
Haass
Christian
C
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
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D019286:Endopeptidase K