Review Article

Current Status of Treatment of Spinal and Bulbar Muscular Atrophy

Figure 1

Potential disease-modifying therapies for spinal and bulbar muscular atrophy (SBMA). Ligand-induced nuclear translocation of mutant androgen receptor (AR) is a critical step of motor neuron degeneration in SBMA. In order to block this step, androgen deprivation therapies using leuprorelin and dutasteride have been developed. AR phosphorylation is another potential treatment strategy through attenuation of ligand binding. Insulin-like growth factor-1 (IGF-1) reduces mutant AR toxicity through phosphorylation of AR at the Akt consensus sites. Amino-terminal (N) and carboxy-terminal (C) (N/C) interaction of mutant AR is critical for toxicity, and this interaction is blocked by selective AR modulators such as RTI-016 and RTI-051b. The SBMA modifier melatonin blocks toxic fibrillar and induces nontoxic annular aggregates. As a transcription factor, the binding of AR to DNA in the nucleus is followed by the recruitment of a variety of transcriptional coregulators. 5-Hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one (ASC-J9) disrupts the interaction between AR and its coregulators and yields a therapeutic effect. In SBMA, histone acetylation is impaired, resulting in transcriptional dysregulation. Sodium butyrate, histone deacetylase (HDAC) inhibitor is effective at this step. Furthermore, transcriptionally attenuated genes such as vascular endothelial growth factor (VEGF), dynactin-1, and transforming growth factor β receptor type II (TGF-βRII) are also possible therapeutic targets. Decreased expression of peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1) is one of the causes of mitochondrial dysfunction, and treatments with the antioxidants coenzyme Q10 and idebenone have been developed targeting mitochondria. Mutant AR is degraded through induction of the ubiquitin-proteasome system (UPS) by acyclic isoprenoid geranylgeranylacetone (GGA) and heat shock protein 90 (Hsp90) inhibitors such as 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG). Autophagy induction using rapamycin and trehalose is also effective for AR degradation in fly and cell models of SBMA. However, the opposite results concerning autophagy augmentation therapy were recently reported in SBMA knock-in mice.
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