Premium
Pathogenesis‐targeting therapeutics for spinal and bulbar muscular atrophy (SBMA)
Author(s) -
Suzuki Keisuke,
Kastuno Masahisa,
Banno Haruhiko,
Sobue Gen
Publication year - 2009
Publication title -
neuropathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.701
H-Index - 61
eISSN - 1440-1789
pISSN - 0919-6544
DOI - 10.1111/j.1440-1789.2009.01013.x
Subject(s) - spinal and bulbar muscular atrophy , polyglutamine tract , androgen receptor , motor neuron , medicine , spinal muscular atrophy , spinal cord , pathology , neuroscience , biology , disease , huntington's disease , prostate cancer , cancer , huntingtin
Spinal and bulbar muscular atrophy (SBMA) is an hereditary, adult‐onset, lower motor neuron disease caused by an aberrant elongation of a trinucleotide CAG repeat, which encodes the polyglutamine tract, in the first exon of the androgen receptor ( AR ) gene. The main symptoms are slowly progressive muscle weakness and atrophy of bulbar, facial and limb muscles. The cardinal histopathological findings of SBMA are an extensive loss of lower motor neurons in the anterior horn of the spinal cord as well as in brainstem motor nuclei and intranuclear accumulations of mutant AR protein in the residual motor neurons. Androgen deprivation therapy rescues neuronal dysfunction in animal models of SBMA, suggesting that the molecular basis for motor neuron degeneration in this disorder is testosterone‐dependent nuclear accumulation of the mutant AR. Suppression of disease progression by leuprorelin acetate has also been demonstrated in a phase 2 clinical trial. In addition, the clarification of pathophysiology leads to appearance of candidate drugs to treat this devastating disease: heat shock protein (HSP) inducer, Hsp90 inhibitor, and histone deacetylase inhibitor. Advances in basic and clinical research on SBMA are now paving the way for clinical application of pathogenesis‐targeting therapeutics.