Open AccessStartle Disease: New Molecular Insights into an Old Neurological Disorder
Author(s) -
Natascha Schaefer,
Robert J. Harvey,
Carmen Villmann
Publication year - 2022
Publication title -
neuroscientist
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.328
H-Index - 125
eISSN - 1089-4098
pISSN - 1073-8584
DOI - 10.1177/10738584221104724
Subject(s) - glycine receptor , neuroscience , gephyrin , postsynaptic potential , inhibitory postsynaptic potential , synaptic cleft , neurotransmission , biology , receptor , glycine , neurotransmitter , genetics , central nervous system , amino acid
Startle disease (SD) is characterized by enhanced startle responses, generalized muscle stiffness, unexpected falling, and fatal apnea episodes due to disturbed feedback inhibition in the spinal cord and brainstem of affected individuals. Mutations within the glycine receptor (GlyR) subunit and glycine transporter 2 (GlyT2) genes have been identified in individuals with SD. Impaired inhibitory neurotransmission in SD is due to pre- and/or postsynaptic GlyR or presynaptic GlyT2 dysfunctions. Previous research has focused on mutated GlyRs and GlyT2 that impair ion channel/transporter function or trafficking. With insights provided by recently solved cryo-electron microscopy and X-ray structures of GlyRs, a detailed picture of structural transitions important for receptor gating has emerged, allowing a deeper understanding of SD at the molecular level. Moreover, studies on novel SD mutations have demonstrated a higher complexity of SD, with identification of additional clinical signs and symptoms and interaction partners representing key players for fine-tuning synaptic processes. Although our knowledge has steadily improved during the last years, changes in synaptic localization and GlyR or GlyT2 homeostasis under disease conditions are not yet completely understood. Combined proteomics, interactomics, and high-resolution microscopy techniques are required to reveal alterations in receptor dynamics at the synaptic level under disease conditions.