Convergence of heat shock protein 90 with ubiquitin in filamentous alpha-synuclein inclusions of alpha-synucleinopathies.
Heat shock proteins (Hsps) facilitate refolding of denatured polypeptides, but there is limited understanding about their roles in neurodegenerative diseases characterized by misfolded proteins. Because Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy are alpha-synucleinopathies characterized by filamentous alpha-synuclein (alpha-syn) inclusions, we assessed which Hsps might be implicated in these disorders by examining human brain samples, transgenic mouse models, and cell culture systems. Light and electron microscopic multiple-label immunohistochemistry showed Hsp90 was the predominant Hsp examined that co-localized with alpha-syn in Lewy bodies, Lewy neurites, and glial cell inclusions and that Hsp90 co-localized with alpha-syn filaments of Lewy bodies in PD. Hsp90 levels were most predominantly increased in PD brains, which correlated with increased levels of insoluble alpha-syn. These alterations in Hsp90 were recapitulated in a transgenic mouse model of PD-like alpha-syn pathologies. Cell culture studies also revealed that alpha-syn co-immunoprecipitated preferentially with Hsp90 and Hsc70 relative to other Hsps, and exposure of cells to proteasome inhibitors resulted in increased levels of Hsp90. These data implicate predominantly Hsp90 in the formation of alpha-syn inclusions in PD and related alpha-synucleinopathies.
Uryu
Kunihiro
K
The Center For Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvania 19104-4283, USA.
Richter-Landsberg
Christiane
C
Welch
William
W
Sun
Eveline
E
Goldbaum
Olaf
O
Norris
Erin H
EH
Pham
Chi-Tuan
CT
Yazawa
Ikuru
I
Hilburger
Kristen
K
Micsenyi
Matthew
M
Giasson
Benoit I
BI
Bonini
Nancy M
NM
Lee
Virginia M-Y
VM
Trojanowski
John Q
JQ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001923:Brain Chemistry; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D061988:Proteasome Inhibitors; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D025801:Ubiquitin / Q000378:metabolism*; D015854:Up-Regulation; D051844:alpha-Synuclein / Q000378:metabolism*
D018841:HSP90 Heat-Shock Proteins; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D051844:alpha-Synuclein