Disorders of synaptic vesicle fusion machinery

Abstract

Neuronal communication relies on the tightly controlled fusion of synaptic vesicles at nerve terminals, which results in the release of neurotransmitters with strict temporal and quantal precision. At rest, synaptic vesicle fusion is inhibited (Brunger et al., 2018). Action potential-mediated opening of voltage-gated Ca 2+ channels results in Ca 2+ influx into the nerve terminal, creating a Ca 2+ nanodomain that triggers the fusion of vesicles that are docked and primed at the plasma membrane, thereby evoking fast synchronous neurotransmitter release (Chanaday & Kavalali, 2018;Sudhof, 2013).Vesicles can additionally fuse asynchronously following evoked synchronous release and some spontaneous fusion of vesicles also occurs, though this is clamped (Chanaday & Kavalali, 2018).These processes are under exquisite regulatory control, preventing excessive neurotransmitter release and ensuring high-fidelity neuronal communication (Brunger et al., 2019;Rizo, 2018;; perturbation of this regulation can lead to a breakdown in neurotransmission.A range of presynaptic proteins are required to orchestrate these precision events. The SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex, composed of the vesicular SNARE protein (v-SNARE) synaptobrevin and the target membrane SNARE proteins (t-SNAREs) syntaxin-1 and SNAP-25 (synaptosomal-associated protein-25), is the core fusion machinery that provides the energy required for fusion of synaptic vesicles with the plasma membrane (Weber et al., 1998). Several other key components regulate synaptic vesicle exocytosis in physiological environments (Brunger et al., 2019;Sudhof, 2014). SNARE complex assembly is orchestrated by Munc13 and Munc18, and further

The Spectrum of PRRT2-Associated Disorders: Update on Clinical Features and Pathophysiology

“…However, the identification of proline-rich transmembrane protein 2 (PRRT2; OMIM * 614386) as the main causative gene for PKD (6) and related disorders (7) argued against the "ion channel hypothesis" (8). In fact, subsequent research has implicated PRRT2 in synapse functioning, which justifies the classification of PRRT2-associated conditions as "synaptopathies, " an emerging rubric of brain disorders (9). Moreover, PRRT2 mutation screening in other episodic neurological disorders has largely expanded its clinical spectrum.…”

Non-Syndromic Intellectual Disability and Its Pathways: A Long Noncoding RNA Perspective

“…Defects on the regulation of synaptic vesicle fusion and exocytosis may be associated with neurodevelopmental disorders, since this is a tightly controlled process necessary for neurotransmitters’ release and neuronal communication [ 158 ]. Neurotransmitter signaling may influence early developmental events, such as proliferation, migration, and differentiation, once they serve as chemical signals in the nervous tissue [ 159 ].…”

Preface to the Special Issue “Presynaptic Dysfunction and Disease”

“…Several decades after these studies, the genetic revolution is now revealing that the core exocytic machinery is perturbed in a wide variety of neurological disorders, including neurodevelopmental, neuromuscular, and neurodegenerative disorders. Melland et al (2020) overview how disturbance of the SV fusion machinery via either toxin action or genetic mutation leads to altered neurotransmitter release and neurological dysfunction.…”

“…They audit the specific mutations across each of the SV fusion proteins and explore the biochemical and physiological mechanisms likely underlying disease pathogenesis. In cataloguing these various neurological disorders associated with dysregulation of the exocytic machinery, Melland et al (2020) reveal common overlapping clinical features that link these seemingly divergent disorders of SV fusion, as well as highlighting some surprising points of heterogeneity. A presynaptic contribution to neurodevelopmental disorders goes much wider, however, than just the disorders of SV fusion outlined above.…”