Neurodegenerative diseases, including Alzheimer's disease, Parkinson disease, ALS, SBMA and so on, are characterized by a common feature of abnormal protein accumulation toxic to neurons. Recently, these abnormal protein-related pathogenesis have been demonstrated to certain extent. However, so far no effective treatment modifying disease process of neurodegeneration (disease-modifying therapy) has developed.
Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease characterized by slowly progressive muscle weakness and atrophy. The cause of this disease is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, within the first exon of the androgen receptor (AR) gene. The CAG repeat has a strong tendency to further expand, accelerating the disease onset with in successive generations.
SBMA exclusively occurs in adult males, whereas both heterozygous and homozygous females are usually asymptomatic. As for a transgenic mouse model of SBMA expressing the full-length human AR containing 97 CAGs (AR-97Q), neuromuscular symptoms are markedly pronounced and accelerated in the male mice. Androgen deprivation through surgical castration or leuprorelin treatment substantially improved the symptoms, histopathological findings, and nuclear accumulation of the pathogenic AR in the male AR-97Q mice. Since the nuclear translocation of AR is ligand-dependent, testosterone appears to show toxic effects by accelerating nuclear translocation of the pathogenic AR.
The ligand-dependent accumulation of the pathogenic AR, an initial step in the neurodegenerative process in SBMA, is followed by several downstream molecular events such as transcriptional dysregulation, axonal transport disruption, and mitochondrial insufficiency, indicating that both upstream and downstream molecular events should be targeted to therapy development. Although the precise mechanism by which motor neurons die remains unclear, activation of cellular defence reactions, ubiquitin-proteasome system, autophagy and heat shock proteins, has been shown to alleviate disease progression in animal models of SBMA.
In this lecture, I present our experience of the development of disease-modifying therapy for SBMA as an example of neurodegenerative diseases.