Hsp70 proteins are composed of an N-terminal ATPase domain and a C-terminal substrate-binding domain (SBD), connected by a short linker region ( Mayer and Bukau, 2005).
A very important class of chaperones is the family of stress-inducible 70 kDa heat-shock proteins (Hsp70s), which have a critical function in a range of cellular processes including the folding of newly synthesized proteins ( Frydman et al, 1994) and the rescue of misfolded proteins ( Gragerov et al, 1992 Mogk et al, 1999), hence avoiding the potentially harmful effects of the aggregation of the latter species ( Hartl, 1996). The pathological conversion of misfolded proteins into cytotoxic species is modulated by interactions with several proteins, among them are molecular chaperones ( Dobson, 2003 Stefani and Dobson, 2003 Young et al, 2004 Balch et al, 2008), which are now recognized as key players in the avoidance of misfolding and hence in protein homeostasis ( Dobson, 2003 Young et al, 2004 Balch et al, 2008). Indeed, αSyn is the major component of Lewy bodies, the protein-rich aggregates found post-mortem in the brains of patients suffering from PD or a number of related diseases. One of the most studied amyloid-forming proteins involved in neurodegeneration is α-synuclein (αSyn), the aggregation of which is linked to the pathogenesis of PD. These disorders, among others, include Alzheimer's (AD), Parkinson's (PD) and Huntington's diseases (HD) ( Chiti and Dobson, 2006 Luheshi et al, 2008). Protein conformational diseases include a range of degenerative disorders in which specific peptides or proteins misfold and aberrantly self-assemble, often in the form of amyloid fibrils, which can be deposited in a variety of tissues, the process of which may lead to toxicity and cell death. Our findings indicate that a decreased expression of Hip could facilitate depletion of Hsp70 by amyloidogenic polypeptides, impairing chaperone proteostasis and stimulating neurodegeneration. Such a co-aggregation phenomenon can be prevented in vitro by the co-chaperone Hip (ST13), and the hypothesis that it might do so also in vivo is supported by studies of a Caenorhabditis elegans model of αSyn aggregation. We show a nucleotide-dependent interaction between Hsp70 and αSyn, which leads to the aggregation of Hsp70, in the presence of ADP along with αSyn. Here, we show that Hsp70 depletion can be a direct result of the presence of aggregation-prone polypeptides. According to in vitro and in vivo models of Parkinson's disease (PD), loss of Hsp70 activity is associated with neurodegeneration and the formation of amyloid deposits of α-synuclein (αSyn), which constitute the intraneuronal inclusions in PD patients known as Lewy bodies. The ATP-dependent protein chaperone heat-shock protein 70 (Hsp70) displays broad anti-aggregation functions and has a critical function in preventing protein misfolding pathologies. Tel.: +44 1223 763070 Fax: +44 1223 336362 E-mail: Department of Structural and Molecular Biology, Institute of Structural and Molecular Biology, University College London, and School of Crystallography, Birkbeck College, Gower Street, London WC1E 6BT, UK. Tel.: +44 1223 336366 Fax: +44 1223 336362 E-mail: of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
*Corresponding authors: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. ‡ These authors contributed equally to this work.5 School of Crystallography, Birkbeck College, University of London, London, UK.4 Research Department of Structural and Molecular Biology, Institute of Structural and Molecular Biology, University College London (UCL), London, UK.3 CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine (CSIC-University of Seville-UPO-Junta de Andalucia), Seville, Spain.2 Department of Genetics, University Medical Centre Groningen and University of Groningen, Groningen, The Netherlands.1 Department of Chemistry, University of Cambridge, Cambridge, UK.
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