Biology subjects

Haghighi, P.

Publications and source records attributed to Haghighi, P..

3 recordsLinked to original sources

bioRxiv2022

A retrograde GCN2/eIF2α, but ATF4 independent, mechanism maintains synaptic strength under acute amino acid scarcity at the NMJ

Neuronal response to nutrient availability plays an important role in the maintenance of cellular homeostasis and behavioral response to the environment in higher eukaryotes. However, we know little about how neuronal function is influenced by acute changes in nutrients at high resolution. Taking advantage of powerful fly genetics and the amenability of the Drosophila larval neuromuscular junction (NMJ), we have investigated the synaptic response to acute amino acid restriction. Our findings indicate that the presence of general control nonderepressible 2 (GCN2) and phosphorylation of its target eukaryotic initiation factor 2 alpha (eIF2) are essential for the ability of the NMJ to maintain normal neurotransmitter output when the larvae are deprived of amino acids. Surprisingly, activating transcription factor 4 (ATF4), which normally acts downstream of GCN2/eIF2, appears dispensable in this regulation. Furthermore, we show that GCN2/eIF2 dependent cascade acts retrogradely from muscle back to motoneuron to adjust synaptic release. These results provide a mechanistic insight into the intricate regulation of synaptic strength through the action of GCN2 when organisms are faced with amino acid scarcity.

neuroscience↗

bioRxiv2022

N6-Adenosine Methylation of SARS-CoV-2 5-UTR Regulates Translation

The coronavirus disease 2019 (COVID19) led to devastating health outcomes and has continued to spread despite global vaccination efforts1. This, alongside the rapid emergence of vaccine resistant variants, creates a need for orthogonal therapeutic strategies targeting more conserved facets of severe acute respiratory syndrome coronavirus (SARS-CoV-2)2-7. The viral genome is a single positive RNA strand divided into a genomic and a subgenomic segment. All 16 non-structural viral proteins are translated from the genomic polycistronic ORFs 1a, and 1b using a single 5'-UTR leader8,9. To our surprise, the full length 5'-UTR efficiently initiates protein translation despite its predicted structural complexity. Through a combination of biochemical assays and bioinformatic analyses, we demonstrate that a single METTL3-dependent m6A methylation event in SARS-CoV-2 5'-UTR regulates the rate of translation initiation. We demonstrate that m6A likely exerts this effect by destabilizing the third stem loop (SL3) and increasing overall accessibility to protein complexes. Our discovery provides a foundational insight into the biology of SARS-CoV-2 by linking m6A modification to its translational regulation and, thus, opens a new avenue for potential novel therapeutic strategies.

molecular biology↗

bioRxiv2018

Rapid active zone remodeling consolidates presynaptic potentiation

Synaptic transmission is mediated by neurotransmitter release at presynaptic active zones (AZs) followed by postsynaptic neurotransmitter detection. Plastic changes in transmission maintain functionality during perturbations and enable memory formation. Postsynaptic plasticity targets neurotransmitter receptors, but presynaptic plasticity mechanisms directly regulating the neurotransmitter release apparatus remain largely enigmatic. Here we describe that AZs consist of nano-modular release site units and identify a molecular sequence adding more modules within minutes of plasticity induction. This requires cognate transport machinery and a discrete subset of AZ scaffold proteins. Structural remodeling is not required for the immediate potentiation of neurotransmitter release, but rather necessary to sustain this potentiation over longer timescales. Finally, mutations in Unc13 that disrupt homeostatic plasticity at the neuromuscular junction also impair shot-term memory when central neurons are targeted, suggesting that both forms of plasticity operate via Unc13. Together, while immediate synaptic potentiation capitalizes on available material, it triggers the coincident incorporation of modular release sites to consolidate stable synapse function.

neuroscience↗