Hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils.
The deposition of protein aggregates in neurons is a hallmark of neurodegenerative diseases caused by polyglutamine (polyQ) proteins. We analyzed the effects of the heat shock protein (Hsp) 70 chaperone system on the aggregation of fragments of huntingtin (htt) with expanded polyQ tracts. In vitro, Hsp70 and its cochaperone Hsp40 suppressed the assembly of htt into detergent-insoluble amyloid-like fibrils in an ATP-dependent manner and caused the formation of amorphous, detergent-soluble aggregates. The chaperones were most active in preventing fibrillization when added during the lag phase of the polymerization reaction. Similarly, coexpression of Hsp70 or Hsp40 with htt in yeast inhibited the formation of large, detergent-insoluble polyQ aggregates, resulting in the accumulation of detergent-soluble inclusions. Thus, the recently established potency of Hsp70 and Hsp40 to repress polyQ-induced neurodegeneration may be based on the ability of these chaperones to shield toxic forms of polyQ proteins and to direct them into nontoxic aggregates.
Muchowski
P J
PJ
Max-Planck-Institut für Biochemie, Department of Cellular Biochemistry, Am Klopferspitz 18A, D-82152 Martinsried, Germany.
Schaffar
G
G
Sittler
A
A
Wanker
E E
EE
Hayer-Hartl
M K
MK
Hartl
F U
FU
D000595:Amino Acid Sequence; D000682:Amyloid / Q000378:metabolism* / Q000648:ultrastructure; D018834:Chaperonin 60 / Q000378:metabolism; D018833:Chaperonins / Q000378:metabolism*; D005091:Exons; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion
D000682:Amyloid; D018834:Chaperonin 60; C494647:DNAJB1 protein, human; D050956:HSP40 Heat-Shock Proteins; C086055:HTT protein, human; D006360:Heat-Shock Proteins; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010455:Peptides; D011993:Recombinant Fusion Proteins; C097188:polyglutamine; D018833:Chaperonins