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Vol. 16, No. 1, 2008
Issue release date: December 2007
Neurosignals 2008;16:63–74
(DOI:10.1159/000109760)

Hsp104: A Weapon to Combat Diverse Neurodegenerative Disorders

Shorter J.
Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pa., USA
email Corresponding Author

Abstract

Many of the fatal neurodegenerative disorders that plague humankind, including Alzheimer’s and Parkinson’s disease, are connected with the misfolding of specific proteins into a surprisingly generic fibrous conformation termed amyloid. Prior to amyloid fiber assembly, many proteins populate a common oligomeric conformation, which may be severely cytotoxic. Therapeutic innovations are desperately sought to safely reverse this aberrant protein aggregation and return proteins to normal function. Whether mammalian cells possess any such endogenous activity remains unclear. By contrast, fungi, plants and bacteria all express Hsp104, a protein-remodeling factor, which synergizes with the Hsp70 chaperone system to resolve aggregated proteins and restore their functionality. Surprisingly, amyloids can also be adaptive. In yeast, Hsp104 directly regulates the amyloidogenesis of several prion proteins, which can confer selective advantages. Here, I review the modus operandi of Hsp104 and showcase efforts to unleash Hsp104 on the protein-misfolding events connected to disparate neurodegenerative amyloidoses.


 goto top of outline Key Words

  • Hsp104
  • Prion
  • Amyloid
  • AAA+ protein
  • Huntington’s disease
  • Neurodegeneration

 goto top of outline Abstract

Many of the fatal neurodegenerative disorders that plague humankind, including Alzheimer’s and Parkinson’s disease, are connected with the misfolding of specific proteins into a surprisingly generic fibrous conformation termed amyloid. Prior to amyloid fiber assembly, many proteins populate a common oligomeric conformation, which may be severely cytotoxic. Therapeutic innovations are desperately sought to safely reverse this aberrant protein aggregation and return proteins to normal function. Whether mammalian cells possess any such endogenous activity remains unclear. By contrast, fungi, plants and bacteria all express Hsp104, a protein-remodeling factor, which synergizes with the Hsp70 chaperone system to resolve aggregated proteins and restore their functionality. Surprisingly, amyloids can also be adaptive. In yeast, Hsp104 directly regulates the amyloidogenesis of several prion proteins, which can confer selective advantages. Here, I review the modus operandi of Hsp104 and showcase efforts to unleash Hsp104 on the protein-misfolding events connected to disparate neurodegenerative amyloidoses.

Copyright © 2008 S. Karger AG, Basel


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 goto top of outline Author Contacts

James Shorter, PhD, Department of Biochemistry and Biophysics
University of Pennsylvania School of Medicine
805b Stellar Chance Laboratories, 422 Curie Boulevard
Philadelphia, PA 19104-6059 (USA)
Tel. +1 215 573 4256, Fax +1 215 898 4217, E-Mail jshorter@mail.med.upenn.edu


 goto top of outline Article Information

Published online: December 5, 2007
Number of Print Pages : 12
Number of Figures : 1, Number of Tables : 0, Number of References : 133


 goto top of outline Publication Details

Neurosignals

Vol. 16, No. 1, Year 2008 (Cover Date: December 2007)

Journal Editor: Ip, N.Y. (Hong Kong)
ISSN: 1424–862X (print), 1424–8638 (Online)

For additional information: http://www.karger.com/NSG


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Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Many of the fatal neurodegenerative disorders that plague humankind, including Alzheimer’s and Parkinson’s disease, are connected with the misfolding of specific proteins into a surprisingly generic fibrous conformation termed amyloid. Prior to amyloid fiber assembly, many proteins populate a common oligomeric conformation, which may be severely cytotoxic. Therapeutic innovations are desperately sought to safely reverse this aberrant protein aggregation and return proteins to normal function. Whether mammalian cells possess any such endogenous activity remains unclear. By contrast, fungi, plants and bacteria all express Hsp104, a protein-remodeling factor, which synergizes with the Hsp70 chaperone system to resolve aggregated proteins and restore their functionality. Surprisingly, amyloids can also be adaptive. In yeast, Hsp104 directly regulates the amyloidogenesis of several prion proteins, which can confer selective advantages. Here, I review the modus operandi of Hsp104 and showcase efforts to unleash Hsp104 on the protein-misfolding events connected to disparate neurodegenerative amyloidoses.



 goto top of outline Author Contacts

James Shorter, PhD, Department of Biochemistry and Biophysics
University of Pennsylvania School of Medicine
805b Stellar Chance Laboratories, 422 Curie Boulevard
Philadelphia, PA 19104-6059 (USA)
Tel. +1 215 573 4256, Fax +1 215 898 4217, E-Mail jshorter@mail.med.upenn.edu


 goto top of outline Article Information

Published online: December 5, 2007
Number of Print Pages : 12
Number of Figures : 1, Number of Tables : 0, Number of References : 133


 goto top of outline Publication Details

Neurosignals

Vol. 16, No. 1, Year 2008 (Cover Date: December 2007)

Journal Editor: Ip, N.Y. (Hong Kong)
ISSN: 1424–862X (print), 1424–8638 (Online)

For additional information: http://www.karger.com/NSG


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

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