|De novo mutations causing aberrant synaptic transmission are increasingly recognized as a cause of developmental and epileptic encephalopathies of infancy and childhood. SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) complex composed of synaptobrevin on the synaptic vesicle and syntaxin and SNAP25 on the plasma membrane, forms the essential fusion machinery for neurotransmitter release. Recent studies have reported 10 different mutations in the gene encoding SNAP25 as a causative factor for these encephalopathies with diverse clinical manifestations and varying severity. However, it remains unclear how SNAP25 mutations give rise to these disorders. Here, we show that specific alterations in action potential-independent spontaneous neurotransmitter release are a key factor in addition to impairments in evoked neurotransmission and may contribute to the disease heterogeneity. We found that structurally clustered mutations in SNAP25 give rise to related synaptic phenotypes by either impairing SNARE-synaptotagmin interactions or SNARE complex zippering that drives membrane fusion. Most importantly, we identified a single mutation that augments spontaneous release without altering evoked release, suggesting that aberrant spontaneous release is sufficient to cause disease in humans. Our results demonstrate that spontaneous neurotransmitter release plays a significant role in the pathophysiology of SNAP25-associated encephalopathies.
B.Alten, Q.Zhou, O.-H.Shin, L.Esquivies, P.-Y.Lin, I.White, R.Sun, W.K.Chung, L.M.Monteggia, A.T.Brunger, E.T.Kavalali. Role of Aberrant Spontaneous Neurotransmission in SNAP25-Associated Encephalopathies. Neuron 109, 59-72 (2021).
6wvw-sf.cif (873.4 KB bytes): Diffraction data for PDB ID 6WVW
6wvw.pdb (751.6 KB bytes): PDB deposition 6WVW