Biology subjects

Erreni, M.

Publications and source records attributed to Erreni, M..

2 recordsLinked to original sources

bioRxiv2026

SUBCELLULAR FUNCTIONS OF UBE3A ISOFORMS DRIVE SYNAPTIC DYSFUNCTION IN ANGELMAN SYNDROME

Genetic defects of the gene encoding the ubiquitin ligase UBE3A cause a severe neurodevelopmental disorder, the Angelman syndrome (AS). The pathophysiology of AS remains unclear, hindering the development of effective therapies. Using AS animal models, we show here that UBE3A controls the development of excitatory and distinct subtypes of inhibitory synapses in cortical pyramidal neurons through cell-autonomous mechanisms, ultimately leading to alteration of synaptic transmission and hyperexcitability. Replacing endogenous Ube3a with individual isoforms, we demonstrate that their uneven nuclear (hUBE3A isoform 1) and cytosolic (hUBE3A isoforms 2/3) distribution is critical for regulating distinct aspects of synaptic development. We also define the molecular requirements underpinning this regulation, showing that: (i) both nuclear and cytosolic UBE3A rely on their ubiquitin ligase activity to ensure proper assembly of synapses; (ii) in addition to the nucleus, UBE3A isoform 1 is also localized in the cytosol, where it is functionally interchangeable with UBE3A isoform 3. Our findings identify a subcellular distribution-dependent mechanism by which UBE3A coordinates cortical circuit development and suggest pathogenic mechanisms of AS.

neuroscience↗

bioRxiv2020

Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia

Neuronal circuits assembly requires the fine equilibrium between synapse formation and elimination. Microglia, through the elimination of supernumerary synapses, have an established role in this process. While the microglial receptor TREM2 and the soluble complement proteins C1q and C3 are recognized key players in this process, the neuronal molecular components that tag synapses to be eliminated are still undefined. Here we show that exposed phosphatidylserine (PS) represents a neuronal eat-me signal enabling microglial-mediated synapse pruning. In hippocampal neuron and microglia co-cultures, synapse elimination can be prevented by blocking accessibility of exposed PS using Annexin V or through microglial loss of TREM2. In vivo, exposed PS is detectable at both hippocampal and retinogeniculate synapses, where exposure coincides with the onset of synapse elimination and increased PS engulfment by microglia. Mice deficient in C1q, which fail to properly refine retinogeniculate connections, display elevated exposed PS and reduced PS engulfment by microglia. These data provide mechanistic insight into microglial-mediated synapse pruning and identify a novel role of developmentally regulated PS exposure that is common among developing brain structures.

neuroscience↗