Biology subjects

Altas, B.

Publications and source records attributed to Altas, B..

3 recordsLinked to original sources

bioRxiv2019

Physiological and pathophysiological homeostasis of astroglial channel proteins by Nedd4-2

Nedd4-2 is an E3 ubiquitin ligase, missense mutation of which is related to familial epilepsy, indicating its critical role in regulating neuronal network activity. However, Nedd4-2 substrates involved in neuronal network function have yet to be identified. Using mouse lines lacking Nedd4-1 and Nedd4-2, we identified astrocytic channel proteins inwardly rectifying K+ channel 4.1 (Kir4.1) and Connexin43 as Nedd4-2 substrates. We found that the expression of Kir4.1 and Connexin43 is increased upon conditional deletion of Nedd4-2 in astrocytes, leading to an elevation of astrocytic membrane ion permeability and gap junction activity, with a consequent reduction of {gamma}-oscillatory neuronal network activity. Interestingly, our biochemical data demonstrate that missense mutations found in familial epileptic patients produce gain-of-function of Nedd4-2 gene product. Our data reveal a process of coordinated astrocytic ion channel proteostasis that controls astrocyte function and astrocyte-dependent neuronal network activity, and elucidate a potential mechanism by which aberrant Nedd4-2 function leads to epilepsy.\n\nCONDENSED TITLEUbiquitination of Astrocytic Channels by Nedd4-2\n\nSUMMARYUbiquitination is a key regulatory machinery for protein expression. Our present work provides evidence that astrocytic ion channel proteostasis coordinated by an E3 ubiquitin ligase Nedd4-2 is of particular importance for the maintenance of neuronal network activity.

neuroscience↗

bioRxiv2019

The Kaufman oculocerebrofacial syndrome protein Ube3b regulates synapse number by ubiquitinating Ppp3cc.

Kaufman oculocerebrofacial syndrome (KOS) is a severe autosomal recessive disorder characterized by intellectual disability, developmental delays, microcephaly and characteristic dysmorphisms. Biallelic mutations of UBE3B, encoding for a ubiquitin ligase E3B are causative for KOS. In this report, we characterize neuronal functions of its murine ortholog Ube3b. We show that Ube3b regulates dendritic branching in a cell-autonomous manner. Moreover, Ube3b knockout (KO) neurons exhibit increased density and aberrant morphology of dendritic spines, altered synaptic physiology and changes in hippocampal circuit activity. Dorsal forebrain-specific Ube3b KO animals show impaired spatial learning and alterations in social interactions. We further demonstrate that Ube3b ubiquitinates the catalytic {gamma}-subunit of calcineurin (Ppp3cc), the overexpression of which phenocopies the loss of Ube3b with regard to dendritic spine density. This work provides insights into the molecular pathologies underlying intellectual disability-like phenotypes in a genetic mouse model for KOS.

neuroscience↗

bioRxiv2019

Correlating Synaptic Ultrastructure and Function at the Nanoscale

Despite similarities in the composition of the molecular release machinery, synapses can exhibit strikingly different functional transmitter release properties and short- and long-term plasticity characteristics. To address the question whether ultrastructural differences could contribute to this functional synaptic heterogeneity, we employed a combination of hippocampal organotypic slice cultures, high-pressure freezing, freeze substitution, and 3D-electron tomography to resolve the spatial organization of vesicle pools at individual active zones (AZ) in two functionally distinct synapses, namely Schaffer collateral (SC) and mossy fiber (MF) synapses. We found that mature MF and SC synapses harbor equal numbers of docked vesicles at their AZs, MF synapses at rest exhibit a second pool of possibly tethered vesicles in the AZ vicinity, and MF synapses contain at least three morphological types of docked vesicles, indicating that differences in the ultrastructural organization of MF and SC synapses may contribute to their respective functional properties and corresponding plasticity characteristics.

neuroscience↗