PT  - JOURNAL ARTICLE
AU  - Christian M. Simon
AU  - Meaghan Van Alstyne
AU  - Francesco Lotti
AU  - Elena Bianchetti
AU  - Sarah Tisdale
AU  - George Z. Mentis
AU  - Livio Pellizzoni
TI  - Stasimon contributes to the loss of sensory synapses and motor neuron death in a mouse model of spinal muscular atrophy
AID  - 10.1101/608513
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 608513
4099  - http://biorxiv.org/content/early/2019/04/13/608513.short
4100  - http://biorxiv.org/content/early/2019/04/13/608513.full
AB  - Reduced expression of the SMN protein causes spinal muscular atrophy (SMA) – an inherited neurodegenerative disease characterized by multiple synaptic deficits and motor neuron loss. Here, we show that AAV9-mediated delivery of Stasimon – a gene encoding an ER-resident transmembrane protein regulated by SMN – improves motor function in a mouse model of SMA through multiple mechanisms. In proprioceptive neurons of SMA mice, Stasimon overexpression prevents the loss of afferent synapses on motor neurons and enhances sensory-motor neurotransmission. In SMA motor neurons, Stasimon suppresses the neurodegenerative process by selectively reducing phosphorylation but not upregulation of the tumor suppressor p53, both of which are converging events required to trigger neuronal death. We further show that Stasimon deficiency synergizes with SMA-related mechanisms of p53 upregulation to induce phosphorylation of p53. These findings identify Stasimon dysfunction induced by SMN deficiency as an upstream driver of cellular pathways that lead to synaptic loss and motor neuron degeneration, revealing a dual contribution of Stasimon to motor circuit pathology in SMA.