| First Author | Tejero R | Year | 2016 |
| Journal | Hum Mol Genet | Volume | 25 |
| Issue | 21 | Pages | 4703-4716 |
| PubMed ID | 28173138 | Mgi Jnum | J:238645 |
| Mgi Id | MGI:5823310 | Doi | 10.1093/hmg/ddw297 |
| Citation | Tejero R, et al. (2016) Synaptotagmin-2, and -1, linked to neurotransmission impairment and vulnerability in Spinal Muscular Atrophy. Hum Mol Genet 25(21):4703-4716 |
| abstractText | Spinal muscular atrophy (SMA) is the most frequent genetic cause of infant mortality. The disease is characterized by progressive muscle weakness and paralysis of axial and proximal limb muscles. It is caused by homozygous loss or mutation of the SMN1 gene, which codes for the Survival Motor Neuron (SMN) protein. In mouse models of the disease, neurotransmitter release is greatly impaired, but the molecular mechanisms of the synaptic dysfunction and the basis of the selective muscle vulnerability are unknown. In the present study, we investigated these open questions by comparing the molecular and functional properties of nerve terminals in severely and mildly affected muscles in the SMNDelta7 mouse model. We discovered that synaptotagmin-1 (Syt1) was developmentally downregulated in nerve terminals of highly affected muscles but not in low vulnerable muscles. Additionally, the expression levels of synaptotagmin-2 (Syt2), and its interacting protein, synaptic vesicle protein 2 (SV2) B, were reduced in proportion to the degree of muscle vulnerability while other synaptic proteins, such as syntaxin-1B (Stx1B) and synaptotagmin-7 (Syt7), were not affected. Consistently with the extremely low levels of both Syt-isoforms, and SV2B, in most affected neuromuscular synapses, the functional analysis of neurotransmission revealed highly reduced evoked release, altered short-term plasticity, low release probability, and inability to modulate normally the number of functional release sites. Together, we propose that the strong reduction of Syt2 and SV2B are key factors of the functional synaptic alteration and that the physiological downregulation of Syt1 plays a determinant role in muscle vulnerability in SMA. |
