Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy.

Abstract

Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ) tract within the androgen receptor. Unifying mechanisms have been implicated in the pathogenesis of polyQ-dependent neurodegenerative diseases including SBMA, Huntington disease and spinocerebellar ataxias. It has been suggested that mutant protein containing polyQ inhibits histone acetyltransferase activity, resulting in transcriptional dysfunction and subsequent neuronal dysfunction. Histone deacetylase (HDAC) inhibitors alleviate neurological phenotypes in fly and mouse models of polyQ disease, although the therapeutic effect is limited by the toxicity of these compounds. We studied the therapeutic effects of sodium butyrate (SB), an HDAC inhibitor, in a transgenic mouse model of SBMA. Oral administration of SB ameliorated neurological phenotypes as well as increased acetylation of nuclear histone in neural tissues. These therapeutic effects, however, were seen only within a narrow range of SB dosage. Our results indicate that SB is a possible therapeutic agent for SBMA and other polyQ diseases, although an appropriate dose should be determined for clinical application.

• Authors: Makoto Minamiyama, Masahisa Katsuno, Hiroaki Adachi, Masahiro Waza, Chen Sang, Yasushi Kobayashi, Fumiaki Tanaka, Manabu Doyu, Akira Inukai, Gen Sobue
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 13 Issue 11 Pg. 1183-92 (Jun 01 2004) ISSN: 0964-6906 [Print] England
• PMID: 15102712 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Butyrates
• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Histones
• Receptors, Androgen

Topics

• Acetylation
• Administration, Oral
• Animals
• Butyrates (administration & dosage, therapeutic use)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (administration & dosage, therapeutic use)
• Gait Ataxia (drug therapy)
• Histone Deacetylase Inhibitors
• Histones (metabolism)
• Intranuclear Inclusion Bodies (drug effects)
• Mice
• Mice, Transgenic
• Motor Neurons (metabolism)
• Muscles (pathology)
• Muscular Disorders, Atrophic (drug therapy, metabolism, pathology)
• Neuroglia (metabolism)
• Receptors, Androgen (metabolism)
• Rotarod Performance Test
• Spinal Cord (pathology)
• Spinal Nerve Roots (pathology)
• Survival Analysis