A5067784942- Cellular transport and secretion
- Lipid Membrane Structure and Behavior
- Neuroscience and Neuropharmacology Research
- Ion channel regulation and function
- Biotin and Related Studies
- RNA regulation and disease
- Calcium signaling and nucleotide metabolism
- Biochemical and Structural Characterization
- RNA Research and Splicing
- Signaling Pathways in Disease
- Microtubule and mitosis dynamics
- Pancreatic function and diabetes
- Erythrocyte Function and Pathophysiology
- RNA modifications and cancer
- Neurological diseases and metabolism
- COVID-19 Clinical Research Studies
- Mitochondrial Function and Pathology
- Amino Acid Enzymes and Metabolism
- Receptor Mechanisms and Signaling
- Pediatric Hepatobiliary Diseases and Treatments
- Genetic Neurodegenerative Diseases
- Vaccine Coverage and Hesitancy
- Endoplasmic Reticulum Stress and Disease
- SARS-CoV-2 and COVID-19 Research
- Myasthenia Gravis and Thymoma
Consejo Nacional de Investigaciones Científicas y Técnicas
2012-2023
Instituto de Histología y Embriología de Mendoza
2012-2023
Yale University
2015-2020
University College London
2017-2020
National Hospital for Neurology and Neurosurgery
2017-2020
Epilepsy Research UK
2018-2020
Universidad Autónoma Metropolitana
2020
Washington Center
2018
University of Washington
2018
Universidad Nacional de Cuyo
2015-2016
Abstract AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca 2+ -impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients intellectual disability (ID) neurodevelopmental...
Significance Synaptotagmin-1 is the calcium sensor for synchronous neurotransmitter release. It couples influx to soluble N -ethylmaleimide–sensitive factor activating protein receptor (SNARE)-catalyzed fusion, but how this coupling happens unknown. Here, using electron microscopy, we report that cytosolic domain of synaptotagmin can assemble into ring-like oligomers under calcium-free conditions, and these rings disassemble rapidly upon binding. This process suggests a novel speculative...
Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 SLC52A3, have recently been linked syndrome. However, the genetic frequency, neuropathology downstream consequences are unclear. By screening large cohort 132 patients early-onset severe motor neuropathy we confirmed...
Hormones and neurotransmitters are released through fluctuating exocytotic fusion pores that can flicker open shut multiple times. Cargo release vesicle recycling depend on the fate of pore, which may reseal or dilate irreversibly. Pore nucleation requires zippering between vesicle-associated v-SNAREs target membrane t-SNAREs, but mechanisms governing subsequent pore dilation not understood. Here, we probed single using v-SNARE-reconstituted ~23-nm-diameter discoidal nanolipoprotein...
We recently reported that the C2AB portion of Synaptotagmin 1 (Syt1) could self-assemble into Ca2+-sensitive ring-like oligomers on membranes, which potentially regulate neurotransmitter release. Here we report analogous assemble from domains other Syt isoforms (Syt2, Syt7, Syt9) as well related C2 domain containing protein, Doc2B and extended Synaptotagmins (E-Syts). Evidently, circular oligomerization is a general conserved structural aspect many proteins, including Synaptotagmins....
Objective To identify disease‐causing variants in autosomal recessive axonal polyneuropathy with optic atrophy and provide targeted replacement therapy. Methods We performed genome‐wide sequencing, homozygosity mapping, segregation analysis for novel gene discovery. used circular dichroism to show secondary structure changes isothermal titration calorimetry investigate the impact of on adenosine triphosphate (ATP) binding. Pathogenicity was further supported by enzymatic assays mass...
Significance Release of neurotransmitters relies on submillisecond coupling synaptic vesicle fusion to the triggering signal: AP-evoked presynaptic Ca 2+ influx. The key player that controls exocytosis is sensor synaptotagmin 1 (Syt1). While activation Syt1 has been extensively characterized, how reversibly clamps vesicular remains enigmatic. Here, using a targeted mutation combined with fluorescence imaging and electrophysiology, we show structural feature self-oligomerize provides...
Significance Synaptotagmin (Syt) is the primary calcium ion (Ca 2+ ) sensor for regulated exocytosis. It couples Ca binding to soluble N -ethylmaleimide–sensitive factor attachment protein receptor-catalyzed fusion, but how this happens unclear. Here, using a targeted mutation combined with single-vesicle fusion optical assay, we show that recently discovered structural feature of Syt self-oligomerize essential coupling vesicular fusion. This suggests an elegant yet simple model in which...
We report 2 families with undiagnosed recessive presynaptic congenital myasthenic syndrome (CMS). Whole exome or genome sequencing identified segregating homozygous variants in VAMP1: c.51_64delAGGTGGGGGTCCCC a Kuwaiti family and c.146G>C an Israeli family. VAMP1 is crucial for vesicle fusion at neuromuscular junction (NMJ). Electrodiagnostic examination showed severely low compound muscle action potentials impairment. assessed the effect of nonsense mutation on mRNA levels evaluated NMJ...
Previously, we showed that synaptotagmin1 (Syt1) forms Ca2+-sensitive ring-like oligomers on membranes containing acidic lipids and proposed a potential role in regulating neurotransmitter release (Zanetti et al., 2016). Here, report Syt1 assembles into similar solution when triggered by naturally occurring polyphosphates (PIP2 ATP) magnesium ions (Mg2+). These soluble rings were observed electron microscopy independently demonstrated quantified using fluorescence correlation spectroscopy....
We report on a homozygous frameshift deletion in DDX59 (c.185del: p.Phe62fs*13) family presenting with orofaciodigital syndrome phenotype associated broad neurological involvement characterized by microcephaly, intellectual disability, epilepsy, and white matter signal abnormalities cortical subcortical ischemic events. encodes DEAD-box RNA helicase its role brain function diseases is unclear. showed reduction of mutant cDNA perturbation SHH signaling from patient-derived cell lines;...
Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino neurotransmitters in brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA CNS, encoded GAD1 gene. Disruption results imbalance excitatory neurotransmitters, as Gad1-/- mice die neonatally severe cleft palate, it has not been possible determine any potential neurological dysfunction. Furthermore, little known...
Progressive limb spasticity and cerebellar ataxia are frequently found together in clinical practice form a heterogeneous group of degenerative disorders that classified either as pure spastic or complex with additional neurological signs. Inheritance is autosomal dominant recessive. Hypomyelinating features on MRI sometimes seen ataxia, but this usually mild adults severe life limiting children. We report seven individuals an early-onset spastic-ataxia phenotype. The come from three...
Abstract The initial, nanometer-sized connection between the plasma membrane and a hormone- or neurotransmitter-filled vesicle –the fusion pore– can flicker open closed repeatedly before dilating resealing irreversibly. Pore dynamics determine release recycling kinetics, but pore properties are poorly known because biochemically defined single-pore assays lacking. We isolated single flickering pores connecting v-SNARE-reconstituted nanodiscs to cells ectopically expressing cognate, “flipped”...
Significance Synaptic transmission depends on all-or-none action potentials. However, subthreshold membrane potential fluctuations at the cell body spread passively along axon and affect shape of presynaptic potentials, calcium influx, neurotransmitter release. Here we apply a superresolution method to identify small terminals for patch clamp. Subthreshold modulation potentials is abolished by mutation in potassium channel Kv1.1 associated with neurological channelopathy episodic ataxia type...
Abstract Synaptotagmin interaction with anionic lipid (phosphatidylserine/phosphatidylinositol) containing membranes, both in the absence and presence of calcium ions (Ca 2+ ), is critical to its central role orchestrating neurotransmitter release. The molecular surfaces involved, namely conserved polylysine motif C2B domain Ca -binding aliphatic loops on C2A domains, are known. Here we use surface force apparatus combined systematic mutational analysis functional directly measure...
Cortical granule exocytosis (CGE), also known as cortical reaction, is a calcium- regulated secretion that represents membrane fusion process during meiotic cell division of oocytes. The molecular mechanism CGE still poorly understood and thought to be mediated by the SNARE pathway; nevertheless, it unkown if SNAP (acronym for soluble NSF attachment protein) N-ethilmaleimide sensitive factor), two key proteins in pathway, mediate any oocyte model. In this paper, we documented gene expression...
Here we introduce ApoE-based nanolipoprotein particle (NLP)-a soluble, discoidal bilayer mimetic of ∼23 nm in diameter, as fusion partners to study the dynamics pores induced by SNARE proteins. Using vitro lipid mixing and content release assays, report that NLPs reconstituted with synaptic v-SNARE VAMP2 (vNLP) fuse liposomes containing cognate t-SNARE (Syntaxin1/SNAP25) partner, resulting pore opening directly external buffer. Efflux encapsulated fluorescent dextrans different sizes show...
Abstract Synaptotagmin1 (Syt1) synchronises neurotransmitter release to action potentials acting as the fast Ca 2+ sensor and inhibitor (clamp) of spontaneous delayed asynchronous release. Whilst Syt1 activation mechanism has been well characterised, how clamps transmitter remains enigmatic. Here we show that C2B domain-dependent oligomerisation provides molecular basis for clamping function. This follows from investigation a designed mutation (F349A), which selectively destabilises...
The population that has not received a SARS-CoV-2 vaccine is at high risk for infection whereas vaccination prevents COVID-19 severe disease, hospitalization, and death. In Argentina, to date, more than 50 million doses of vaccines against have been administered. three main applied are Sputnik V, Oxford-AstraZeneca, Sinopharm. this study, we compared the antibody response voluntary individuals day 0 (first dose day) 21-25 days post first second dose. Our results indicate after administration...