Biology subjects

Aly, A.

Publications and source records attributed to Aly, A..

4 recordsLinked to original sources

bioRxiv2026

Conformation Driven Enhancement of Neurolysin Activity in Presence of a Small Molecule Activator

Neurolysin (Nln) is an M3 metallopeptidase that regulates neuropeptide concentration in the central nervous system. It has emerged as a therapeutic target for mitigating post-ischemic injury by hydrolyzing and inactivating several neuropeptides. It has been recently shown that small molecule activators, such as pyridine piperazine (Py-Pip) derivatives, can enhance Nln catalytic activity, facilitating hydrolysis of Nln substrate peptides. However, binding sites of these molecules and the mechanism of action remain unclear due to the dynamic nature of Nln. Here, we use molecular dynamics (MD) simulation of the apo and activator-bound Nln systems along with Markov state modeling to identify three binding sites of Py-Pip, and quantify their effects on the Nln conformational landscape and kinetics. Two of these sites have opposing functional outcomes: Binding inside the interhelical channel favors closed conformations by slowing down channel opening, thus allowing the substrates to orient favorably for the catalytic reaction, while binding at the exterior region of the channel stabilizes open states, potentially facilitating both substrate entry and cleaved product release. These findings suggest a possibility of a multi-site allosteric activation model in which distinct binding locations selectively modulate different steps within a catalytic cycle. This framework provides a structural and kinetic model for the action of small molecule Nln activators, offering insight into the design of cerebro-protective therapeutics that reduce neuropeptide accumulation after ischemic injury.

biophysics↗

bioRxiv2024

FUS controls muscle differentiation and structure through LLPS mediated recruitment of MEF2 and ETV5

FUS is an RNA binding protein mutated in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive muscle weakness. We show that ALS-associated FUS mutations lead to ultrastructural defects in muscle of FUS-ALS patients, with disruption of sarcomeres and mitochondria. Studies in mouse and Drosophila models demonstrate an evolutionary-conserved cell autonomous function of FUS in muscle development. Mechanistically, FUS is required for transcription of MEF2 dependent genes, binds to the promoter of genes bound by ETS transcription factors in particular ETV5 and co-activates transcription of MEF2 dependent genes with ETV5. FUS phase separates with ETV5 and MEF2A, and MEF2A binding to FUS is potentiated by ETV5. Last, Etv5 haploinsufficiency exacerbates muscle weakness in a mouse model of FUS-ALS. These findings establish FUS as an essential protein for skeletal muscle structure through its phase separation-dependent recruitment of ETV5 and MEF2, defining a novel pathway compromised in FUS-ALS.

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↗

bioRxiv2021

Neuron-Glia Signaling Regulates the Onset of the Antidepressant Response

Commonly prescribed antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) take weeks to achieve therapeutic benefits1, 2. The underlying mechanisms of why antidepressants take weeks or months to reverse depressed mood are not understood. Using a single cell sequencing approach, we analyzed gene expression changes in mice subjected to stress-induced depression and determined their temporal response to antidepressant treatment in the cerebral cortex. We discovered that both glial and neuronal cell populations elicit gene expression changes in response to stress, and that these changes are reversed upon treatment with fluoxetine (Prozac), a widely prescribed selective serotonin reuptake inhibitor (SSRI). Upon reproducing the molecular signaling events regulated by fluoxetine3 in a cortical culture system, we found that these transcriptional changes are serotonin-dependent, require reciprocal neuron-glia communication, and involve temporally-specified sequences of autoregulation and cross-regulation between FGF2 and BDNF signaling pathways. Briefly, stimulation of Fgf2 synthesis and signaling directly regulates Bdnf synthesis and secretion cell-non-autonomously requiring neuron-glia interactions, which then activates neuronal BDNF-TrkB signaling to drive longer-term neuronal adaptations4-6 leading to improved mood. Our studies highlight temporal and cell type specific mechanisms promoting the onset of the antidepressant response, that we propose could offer novel avenues for mitigating delayed onset of antidepressant therapies.

neuroscience↗