Alleviating neurodegeneration by an anticancer agent: an Hsp90 inhibitor (17-AAG)

Ann N Y Acad Sci. 2006 Nov;1086:21-34. doi: 10.1196/annals.1377.012.

Abstract

Heat shock proteins (HSPs) that function mainly as molecular chaperones play an important role in the folding and quality control of proteins. Compared with these chaperones, Hsp90 is unique in that it binds to substrate proteins, called Hsp90 client proteins. Hsp90 is involved in the folding, activation, and assembly of its client proteins in association with its co-chaperones. Because numerous oncoproteins belonging to the Hsp90 client protein family are selectively degraded by Hsp90 inhibitors, 17-allylamino-17-demethoxygeldanamycin (17-AAG), a first-in-class Hsp90 inhibitor, is now under clinical trials as a novel molecular-targeted agent for a wide range of malignancies. In spinal and bulbar muscular atrophy (SBMA), the pathogenic gene product is polyglutamine (polyQ)-expanded androgen receptor (AR), which belongs to the Hsp90 client protein family and is known to be degraded by 17-AAG. We have recently demonstrated that administration of an anticancer agent 17-AAG significantly ameliorated polyQ-mediated motor neuron degeneration by reducing the total amount of mutant AR. The ability of 17-AAG to degrade mutant protein would be directly applicable to SBMA and other neurodegenerative diseases in which the disease-causing proteins also belong to the Hsp90 client protein family. Our proposed therapeutic approach using a novel anticancer agent 17-AAG has emerged as a candidate for molecular-targeted therapies for neurodegenerative diseases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Benzoquinones / pharmacology
  • Benzoquinones / therapeutic use*
  • Bulbar Palsy, Progressive / drug therapy
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Humans
  • Lactams, Macrocyclic / pharmacology
  • Lactams, Macrocyclic / therapeutic use*
  • Mice
  • Motor Neurons / drug effects
  • Muscular Atrophy, Spinal / drug therapy
  • Mutation
  • Neurodegenerative Diseases / drug therapy*
  • Proteasome Endopeptidase Complex / metabolism
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism

Substances

  • AR protein, human
  • Antineoplastic Agents
  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • Receptors, Androgen
  • tanespimycin
  • Proteasome Endopeptidase Complex