Accumulation of phosphorylated alpha-synuclein in aging human brain.
Alpha-synuclein in Lewy bodies (LBs) is phosphorylated at Ser129. We raised monoclonal and polyclonal antibodies to this phosphorylation site (psyn) and examined 157 serial autopsy brains from a geriatric hospital. Anti-psyn immunoreactivity was observed in 40 of these cases (25.5%). Immunohistochemistry revealed 4 novel types of pathology: diffuse neuronal cytoplasmic staining (pre-LB); neuropil thread-like structures (Lewy threads); dot-like structures similar to argyrophilic grains (Lewy dots); and axons in the white matter (Lewy axons). This novel pathology was abundantly present around LBs and also involved the limbic subcortical white matter, the cerebral cortical molecular layer, and the spongiform changes of the medial temporal lobe associated with cases of dementia with LBs (DLB). The phosphorylated alpha-synuclein was limited to the temporal lobe in cases of Parkinson disease, spread from the temporal lobe to the frontal lobe in cases of DLB transitional form and further spread to the parietal and occipital lobes in DLB neocortical form. Our findings suggest that LB-related pathology initially involves the neuronal perikarya, dendrites, and axons, causes impairment of axonal transport and synaptic transmission, and later leads to the formation of LBs, a hallmark of functional disturbance long before neuronal cell death.
Saito
Yuko
Y
Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.
Kawashima
Akiko
A
Ruberu
Nyoka N
NN
Fujiwara
Hideo
H
Koyama
Shunichi
S
Sawabe
Motoji
M
Arai
Tomio
T
Nagura
Hiroshi
H
Yamanouchi
Hiroshi
H
Hasegawa
Masato
M
Iwatsubo
Takeshi
T
Murayama
Shigeo
S
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000911:Antibodies, Monoclonal; D001369:Axons / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D003704:Dementia / Q000378:metabolism / Q000473:pathology; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000276:immunology / Q000378:metabolism*; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D051843:Synucleins; D051844:alpha-Synuclein
D000911:Antibodies, Monoclonal; D005456:Fluorescent Dyes; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein