Alpha-synuclein and chaperones in dementia with Lewy bodies.
The protein alpha-synuclein (ASYN) is thought to be involved in the development of dementia with Lewy bodies (DLB). Overexpression of ASYN has been linked to cellular toxicity and human disease, and in experimental models, chaperones such as heat shock proteins (HSPs) are protective against ASYN toxicity. We have assessed the abundance of mRNA for ASYN and chaperones and the abundance and solubility of the encoded proteins in temporal cortex from sporadic human DLB. We found a reduction of ASYN mRNA in DLB (44.9% of control). The abundance of the Triton-soluble fraction (bioavailable protein) was not altered, but there was an increase of the Triton-insoluble component (likely representing aggregates). We evaluated 3 chaperones: HSP70, HSP90, and HDJ1. HSP70 mRNA was increased in DLB, whereas the mRNAs for HSP90 and HDJ1 were unchanged. HSP70 accumulated in the Triton-soluble fraction, whereas HSP90 and HDJ1 proteins accumulated in the Triton-insoluble fraction. These observations suggest that sporadic DLB is not associated with overexpression of ASYN. Rather, the persistence of normal soluble ASYN protein levels, despite the reduction of its mRNA, suggests a primary defect in clearance of the protein. However, this reduced clearance cannot be attributed to a failure of chaperone expression, because their mRNA is unchanged or increased in the DLB brain.
Cantuti-Castelvetri
Ippolita
I
Massachusetts General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Klucken
Jochen
J
Ingelsson
Martin
M
Ramasamy
Karunya
K
McLean
Pamela J
PJ
Frosch
Matthew P
MP
Hyman
Bradley T
BT
Standaert
David G
DG
D016022:Case-Control Studies; D003902:Detergents; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020961:Lewy Body Disease / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D017830:Octoxynol; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D012995:Solubility; D013702:Temporal Lobe / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
C494647:DNAJB1 protein, human; D003902:Detergents; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D012333:RNA, Messenger; D051844:alpha-Synuclein; D017830:Octoxynol