[Development of therapeutics for spinal and bulbar muscular atrophy (SBMA)].

Abstract

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a hereditary motor neuron disease that affects males, caused by the expansion of a polyglutamine (polyQ) tract in androgen receptor (AR). Female carriers are usually asymptomatic. The transgenic mouse (Tg) model carrying a full-length human AR with expanded polyQ has significant gender-related motor impairment. This phenotype is inhibited by castration, which prevents nuclear translocation of mutant AR. Leuprorelin, an LHRH agonist that reduces testosterone release from the testis, also rescues motor dysfunction and nuclear accumulation of mutant AR in the male Tg. Over-expression of a molecular chaperone HSP70, which renatures misfolded mutant AR, ameliorates neuromuscular phenotypes of the Tg by reducing nuclear-localized mutant AR. HSP70 appears to enhance the degradation of mutant AR via ubiquitin-proteasome pathway. These experimental approaches indicate the possibility of clinical application of drugs, such as leuprorelin, for SBMA patients.

• Authors: Gen Sobue
• Journal: Rinsho shinkeigaku = Clinical neurology (Rinsho Shinkeigaku) Vol. 43 Issue 11 Pg. 909-11 (Nov 2003) ISSN: 0009-918X [Print] Japan
• PMID: 15152501 (Publication Type: Journal Article, Review)

Chemical References

• HSP70 Heat-Shock Proteins
• Multienzyme Complexes
• Peptides
• Receptors, Androgen
• Ubiquitin
• polyglutamine
• Gonadotropin-Releasing Hormone
• Testosterone
• Cysteine Endopeptidases
• Proteasome Endopeptidase Complex
• Leuprolide

Topics

• Animals
• Castration
• Cysteine Endopeptidases (metabolism)
• Disease Models, Animal
• Female
• Gonadotropin-Releasing Hormone (agonists)
• HSP70 Heat-Shock Proteins (pharmacology, therapeutic use)
• Humans
• Leuprolide (pharmacology, therapeutic use)
• Male
• Mice
• Mice, Transgenic
• Multienzyme Complexes (metabolism)
• Muscular Disorders, Atrophic (genetics, therapy)
• Mutation
• Peptides (genetics)
• Proteasome Endopeptidase Complex
• Receptors, Androgen (genetics, metabolism)
• Testis (metabolism)
• Testosterone (metabolism)
• Trinucleotide Repeat Expansion
• Ubiquitin (metabolism)