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(American Journal of Pathology. 2006;168:947-961.)
© 2006 American Society for Investigative Pathology

Convergence of Heat Shock Protein 90 with Ubiquitin in Filamentous {alpha}-Synuclein Inclusions of {alpha}-Synucleinopathies

Kunihiro Uryu*, Christiane Richter-Landsberg{dagger}, William Welch{ddagger}, Eveline Sun*, Olaf Goldbaum{dagger}, Erin H. Norris*, Chi-Tuan Pham*, Ikuru Yazawa*, Kristen Hilburger*, Matthew Micsenyi*, Benoit I. Giasson§, Nancy M. Bonini, Virginia M.-Y. Lee* and John Q. Trojanowski*||

From The Center for Neurodegenerative Disease Research,* the Institute of Aging,|| the Department of Pharmacology,§ and the Department of Biology and Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania; the Department of Medicine and Physiology,{ddagger} University of California, San Francisco, California; and the Department of Biology,{dagger} University of Oldenburg, Oldenburg, Germany

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.




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