Restoring early postnatal synaptic dysregulation rescues motor neuron degeneration in a mouse model of Spinal and Bulbar Muscular Atrophy

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disorder caused by expansion of a polyglutamine tract in the androgen receptor (AR). Here, we show that polyglutamine-expanded AR accumulates in the nucleus of motor neurons and induces aberrant upregulation of glutamatergic synaptic genes through dysfunction of the master transcriptional repressor REST during early postnatal development in a mouse model of SBMA (AR-97Q mice). Reducing mutant AR or restoring REST function using antisense oligonucleotides during the neonatal period attenuated the upregulation of glutamatergic synaptic genes and ameliorated the disease phenotype and histopathology in AR-97Q mice. Furthermore, we observed increased calcium activity in induced pluripotent stem cell-derived motor neurons from SBMA patients compared to those from healthy controls, reflecting neuronal hyperexcitability. Late-onset neurodegeneration in SBMA is attributable to early synaptic defects and the resulting hyperexcitability of motor neurons, which may represent therapeutic targets. Early synaptic dysregulation underlies late-onset neurodegeneration in SBMA. Aberrant upregulation of REST target glutamatergic synaptic genes by polyglutamine-expanded AR induces motor neuron hyperexcitability, highlighting a therapeutic window.