Hsp70 and Hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils

Citation
Pj. Muchowski et al., Hsp70 and Hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils, P NAS US, 97(14), 2000, pp. 7841-7846
Citations number
34
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN journal
0027-8424 → ACNP
Volume
97
Issue
14
Year of publication
2000
Pages
7841 - 7846
Database
ISI
SICI code
0027-8424(20000705)97:14<7841:HAHCCI>2.0.ZU;2-5
Abstract
The deposition of protein aggregates in neurons is a hallmark of neurodegen erative diseases caused by polyglutamine (polyQ) proteins. We analyzed the effects of the heat shock protein (Hsp) 70 chaperone system on the aggregat ion of fragments of huntingtin (htt) with expanded polyQ tracts. In vitro, Hsp70 and its cochaperone Hsp40 suppressed the assembly of htt into deterge nt-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 wit h 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 t o shield toxic forms of polyQ proteins and to direct them into nontoxic agg regates.