TorsinA and heat shock proteins act as molecular chaperones: suppression of alpha-synuclein aggregation.
TorsinA, a protein with homology to yeast heat shock protein104, has previously been demonstrated to colocalize with alpha-synuclein in Lewy bodies, the pathological hallmark of Parkinson's disease. Heat shock proteins are a family of chaperones that are both constitutively expressed and induced by stressors, and that serve essential functions for protein refolding and/or degradation. Here, we demonstrate that, like torsinA, specific molecular chaperone heat shock proteins colocalize with alpha-synuclein in Lewy bodies. In addition, using a cellular model of alpha-synuclein aggregation, we demonstrate that torsinA and specific heat shock protein molecular chaperones colocalize with alpha-synuclein immunopositive inclusions. Further, overexpression of torsinA and specific heat shock proteins suppress alpha-synuclein aggregation in this cellular model, whereas mutant torsinA has no effect. These data suggest that torsinA has chaperone-like activity and that the disease-associated GAG deletion mutant has a loss-of-function phenotype. Moreover, these data support a role for chaperone proteins, including torsinA and heat shock proteins, in cellular responses to neurodegenerative inclusions.
McLean
Pamela J
PJ
Alzheimer's Disease Research Unit, Center for Aging, Genetics and Neurodegeneration, Massachusetts General Hospital East, Charlestown, Massachusetts 02129, USA.
Kawamata
Hibiki
H
Shariff
Saadat
S
Hewett
Jeffrey
J
Sharma
Nutan
N
Ueda
Kenji
K
Breakefield
Xandra O
XO
Hyman
Bradley T
BT
D000544:Alzheimer Disease / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology; D020961:Lewy Body Disease / Q000473:pathology*; D046911:Macromolecular Substances; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017510:Protein Folding; D013378:Substantia Nigra / Q000473:pathology; D051843:Synucleins; D014162:Transfection; D051844:alpha-Synuclein
D002352:Carrier Proteins; D006360:Heat-Shock Proteins; D046911:Macromolecular Substances; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C118958:SNCAIP protein, human; D051843:Synucleins; C108175:TOR1A protein, human; D051844:alpha-Synuclein