Altered ionic currents and amelioration by IGF-1 and PACAP in motoneuron-derived cells modelling SBMA.

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a motor neuron disease caused by the expansion of a polymorphic CAG tandem repeat encoding a polyglutamine (polyQ) tract in the androgen receptor (AR) gene. SBMA is triggered by the binding of mutant AR to its natural ligands, testosterone and dihydrotestosterone (DHT). To investigate the neuronal alterations of motor neuron cell models of SBMA, we applied patch-clamp methods to verify how polyQ expansions in the AR alter cell ionic currents. We used mouse motoneuron-derived MN-1 cells expressing normal AR (MN24Q) and mutant AR (MN100Q treated cells with vehicle EtOH and DHT). We observed a reduction of the current flux mainly at depolarizing potentials in the DHT-treated cells, while the dissection of macroscopic currents showed single different cationic currents belonging to voltage-gated channels. Also, we treated the cells with IGF-1 and PACAP, which have previously been shown to protect MN-1 cells from the toxicity of mutant AR, and we found an amelioration of the altered currents. Our results suggest that the electrophysiological correlate of SBMA is a suitable reference point for the identification of disease symptoms and for future therapeutic targets.