Cepharanthine hydrochloride degrades polyglutamine-expanded androgen receptor proteins through an autophagy pathway...

Cepharanthine is a biscoclaurine alkaloid extracted from Stephania cepharantha that has a variety of biological activities in multiple diseases. Spinal and bulbar muscular atrophy (SBMA) is a late-onset neurodegenerative neuromuscular disease without effective therapy, and the protein toxicity of androgen-dependent polyglutamine-expanded androgen receptor is thought to contribute to its etiology. To determine the therapeutic potential of cepharanthine in SBMA, a murine neuron cell model of SBMA was set up, bearing the human polyglutamine-expanded androgen receptor gene with the Tet-On system. Using this model, we found that the semi-synthetic cepharanthine derivative, cepharanthine hydrochloride (CH), decreased protein levels of polyglutamine-expanded androgen receptor in the cytoplasm and nucleus. Mechanically, CH induced intact autophagy flux and enhanced the clearance of cytoplasmic polyglutamine-expanded androgen receptor, which is different from ubiquitin/proteasome degradation of wild-type androgen receptor. Autophagy induced by CH exhibited cellular protective effects against cytotoxicity of mutant androgen receptor as shown by reduced apoptotic marker and apoptotic cell count. Additionally, activities of cell energy sensor-AMPK signal and intracellular ATP were diminished under CH treatment. In conclusion, this study showed that CH degraded polyglutamine-expanded androgen receptor proteins through an autophagy pathway in neuron cells, resulting in cellular protective effects against toxicity of polyQ expanded proteins. These findings may provide new strategies for the treatment of SBMA and other autophagy-related diseases. Furthermore, the clinical safety and compliance of cepharanthine may make it preferable to current autophagy inducers that may cause undesirable side effects in the treatment of autophagy-related diseases.