Biology subjects

Saber, S. H.

Publications and source records attributed to Saber, S. H..

4 recordsLinked to original sources

bioRxiv2024

Saturated fatty acid-Coenzyme A supplementation restores neuronal energy levels and protein homeostasis in hereditary spastic paraplegia

Mitochondrial ATP production is fuelled by a fatty acid flux generated by phospholipase and triglyceride lipases in metabolically demanding tissues such as heart and liver, while the brain has long been believed to use almost solely glucose for energy. Phospholipase A1 enzyme DDHD2 is a major triglyceride lipase in the brain, and the loss of DDHD2 function results in a saturated free fatty acid (sFFA) imbalance and lipid droplet (LD) accumulation in the brain. The LD accumulation in neurons has been enigmatic as LDs are mainly considered to serve as a fuel storage. Here, we demonstrate that the loss of DDHD2 results in a mitochondrial respiratory dysfunction that leads to a significant decrease in ATP production and acetyl coenzyme A levels in neurons, even when the glycolytic breakdown of glycose occurs normally. Loss of DDHD2 also leads to a presynaptic defect as well as an imbalance in the global protein homeostasis in the neurons. These defects were rescued by external supplementation of the sFFA myristic acid coupled with its cofactor coenzyme A (Myr-CoA), indicating sFFA fuelling for neuronal {beta}-oxidation. We have thus discovered that the sFFAs released by the activity of DDHD2 play a central role in providing energy to fuel synaptic function. One Sentence SummaryFree fatty acids released by DDHD2 activity play a central role in maintaining neuronal energy levels and synaptic function.

neuroscience↗

bioRxiv2023

Complete Protection from SARS-CoV-2 Lung Infection in Mice Through Combined Intranasal Delivery of PIKfyve Kinase and TMPRSS2 Protease Inhibitors

Emerging variants of concern of SARS-CoV-2 can significantly reduce the prophylactic and therapeutic efficacy of vaccines and neutralizing antibodies due to mutations in the viral genome. Targeting cell host factors required for infection provides a complementary strategy to overcome this problem since the host genome is less susceptible to variation during the life span of infection. The enzymatic activities of the endosomal PIKfyve phosphoinositide kinase and the serine protease TMPRSS2 are essential to meditate infection in two complementary viral entry pathways. Simultaneous inhibition in cultured cells of their enzymatic activities with the small molecule inhibitors apilimod dimesylate and nafamostat mesylate synergistically prevent viral entry and infection of native SARS-CoV-2 and vesicular stomatitis virus (VSV)-SARS-CoV-2 chimeras expressing the SARS-CoV-2 surface spike (S) protein and of variants of concern. We now report prophylactic prevention of lung infection in mice intranasally infected with SARS-CoV-2 beta by combined intranasal delivery of very low doses of apilimod dimesylate and nafamostat mesylate, in a formulation that is stable for over 3 months at room temperature. Administration of these drugs up to 6 hours post infection did not inhibit infection of the lungs but substantially reduced death of infected airway epithelial cells. The efficiency and simplicity of formulation of the drug combination suggests its suitability as prophylactic or therapeutic treatment against SARS-CoV-2 infection in households, point of care facilities, and under conditions where refrigeration would not be readily available.

microbiology↗

bioRxiv2023

DDHD2 interacts with STXBP1 to mediate long-term memory via the generation of myristic acid

The phospholipid and free fatty acid (FFA) composition of neuronal membranes plays a crucial role in learning and memory, but the mechanisms through which neuronal activity affects the brains lipid landscape remain largely unexplored. Saturated FFAs, particularly myristic acid (C14:0), strongly increase during neuronal stimulation and memory acquisition, suggesting the involvement of phospholipase A1 (PLA1) activity in synaptic plasticity. Here, we show that genetic ablation of the DDHD2 isoform of PLA1 in mice reduced memory performance in reward-based learning and spatial memory models prior to the development of neuromuscular deficits, and markedly reduced saturated FFAs across the brain. DDHD2 was shown to bind to the key synaptic protein STXBP1. Using STXBP1/2 knockout neurosecretory cells and a haploinsufficient STXBP1+/- mouse model of STXBP1 encephalopathy that is also associated with intellectual disability and motor dysfunction, we show that STXBP1 controls the targeting of DDHD2 to the plasma membrane and the generation of saturated FFAs in the brain. Our findings suggest key roles for DDHD2 and STXBP1 in the lipid metabolism underlying synaptic plasticity, learning and memory.

neuroscience↗

bioRxiv2023

The infectivity of SARS-CoV-2 progeny virions requires the activity of host cell N-myristoyltransferases and it is severely compromised by their inhibition

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the coronavirus disease 2019 (COVID-19) pandemic, remains a global health concern despite vaccines, neutralizing antibodies, and antiviral drugs. Emerging mutations can reduce the effectiveness of these treatments, suggesting that targeting host cell factors may be a valuable alternative. N-myristoyltransferases (NMT) are essential enzymes for protein N-myristoylation, affecting stability, interaction, localization, and function of numerous proteins. We demonstrate that selective inhibition of host cell NMT decreases SARS-CoV-2 infection by 90% in human lung and primary nasal epithelial cells, and choroid plexus-cortical neuron organoids. NMT inhibition does not affect viral entry, replication or release, but impairs the maturation and incorporation of viral envelope proteins into newly assembled virions, leading to compromised infectivity of released virions. The inhibition of host NMT triggers a Golgi-bypassing pathway for SARS-CoV-2 progeny virion egress, which occurs through endoplasmic reticulum and lysosomal intermediates.

microbiology↗