Stasimon Contributes to the Loss of Sensory Synapses and Motor Neuron Death in a Mouse Model of Spinal Muscular Atrophy

• Published in: Cell reports (Cambridge) 2019-12, Vol.29 (12), p.3885-3901.e5
• Main Authors: Simon, Christian M., Van Alstyne, Meaghan, Lotti, Francesco, Bianchetti, Elena, Tisdale, Sarah, Watterson, D. Martin, Mentis, George Z., Pellizzoni, Livio
• Format: Article
• Language: English
• Subjects: Animals; Dependovirus - genetics; Membrane Proteins - administration & dosage; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; motor neurons; Motor Neurons - metabolism; Motor Neurons - pathology; Muscular Atrophy, Spinal - etiology; Muscular Atrophy, Spinal - metabolism; Muscular Atrophy, Spinal - pathology; neurodegeneration; p38 MAPK; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; p53; proprioceptive neurons; Sensory Receptor Cells - metabolism; Sensory Receptor Cells - pathology; SMN; spinal muscular atrophy; Stasimon; Survival of Motor Neuron 1 Protein - physiology; Synapses - metabolism; Synapses - pathology; Tmem41b; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.11.058

Reduced expression of the survival motor neuron (SMN) protein causes the neurodegenerative disease spinal muscular atrophy (SMA). Here, we show that adeno-associated virus serotype 9 (AAV9)-mediated delivery of Stasimon—a gene encoding an endoplasmic reticulum (ER)-resident transmembrane protein regulated by SMN—improves motor function in a mouse model of SMA through multiple mechanisms. In proprioceptive neurons, Stasimon overexpression prevents the loss of afferent synapses on motor neurons and enhances sensory-motor neurotransmission. In motor neurons, Stasimon suppresses neurodegeneration by reducing phosphorylation of the tumor suppressor p53. Moreover, Stasimon deficiency converges on SMA-related mechanisms of p53 upregulation to induce phosphorylation of p53 through activation of p38 mitogen-activated protein kinase (MAPK), and pharmacological inhibition of this kinase prevents motor neuron death in SMA mice. These findings identify Stasimon dysfunction induced by SMN deficiency as an upstream driver of distinct cellular cascades that lead to synaptic loss and motor neuron degeneration, revealing a dual contribution of Stasimon to motor circuit pathology in SMA. [Display omitted] •AAV9-mediated Stasimon expression improves motor function in SMA mice•Stasimon contributes to deafferentation and motor neuron death in SMA mice•Stasimon deficiency induces p53 phosphorylation through p38 MAPK activation•Pharmacological inhibition of p38 MAPK prevents neurodegeneration in SMA mice SMN deficiency causes motor circuit dysfunction in SMA. Simon et al. show that Stasimon—an ER-resident protein regulated by SMN—contributes to sensory synaptic loss and motor neuron death in SMA mice through distinct mechanisms. In motor neurons, Stasimon dysfunction induces p38 MAPK-mediated phosphorylation of p53 whose inhibition prevents neurodegeneration.