Biology subjects

Yak, N.

Publications and source records attributed to Yak, N..

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

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↗

bioRxiv2022

Surface SV2A-Syt1 nanoclusters act as a sequestration hub that limits dynamin-1 recruitment and targeting to recycling synaptic vesicles

Following exocytosis, the recapture of plasma membrane-stranded vesicular proteins into recycling synaptic vesicles (SVs) is essential for sustaining neurotransmission. Surface clustering of vesicular proteins has been postulated as a pre-assembly mechanism for endocytosis - ensuring high-fidelity retrieval. Here, we used single-molecule imaging to examine the nanoclustering of synaptotagmin-1 (Syt1) and synaptic vesicle protein 2A (SV2A) in hippocampal neurons. Syt1 forms surface nanoclusters through interaction of its C2B domain with SV2A, that are sensitive to mutations in this domain (Syt1K326A/K328A) and knocking down SV2A. SV2A co-cluster with Syt1 and blocking SV2As cognate interaction with Syt1 (SV2AT84A) also decreased SV2A clustering. Surprisingly, impairing SV2A-Syt1 nanoclustering enhanced plasma membrane recruitment of key endocytic protein dynamin-1, leading to accelerated Syt1 endocytosis, altered intracellular sorting and decreased trafficking of Syt1 to Rab5-positive endocytic compartments. SV2A-Syt1 surface nanoclusters therefore negatively regulate the rate of their own re-entry into recycling SVs by controlling the recruitment of the endocytic machinery.

neuroscience↗

bioRxiv2021

SV2A-Syt1 interaction controls surface nanoclustering and access to recycling synaptic vesicles

Following exocytosis, the recapture of vesicular proteins stranded at the plasma membrane in recycling synaptic vesicles (SVs) is essential to sustain neurotransmission. Nanoclustering is emerging as a mechanism through which proteins may be pre-assembled prior to endocytosis, to ensure high fidelity of retrieval for subsequent rounds of vesicle fusion. Here, we used single molecule imaging to examine the nanoclustering of synaptotagmin-1 (Syt1) and synaptic vesicle protein 2A (SV2A). Syt1 forms surface nanoclusters through interaction of its C2B domain (K326/K328) with SV2A, as demonstrated by mutating Syt1 (K326A/K328A) and knocking down endogenous SV2A. Blocking cognate interaction with Syt1 (SV2AT84A) also decreased SV2A clustering. Impaired nanoclustering of Syt1 and SV2A leads to accelerated endocytosis of Syt1, altered intracellular sorting and decreased trafficking of Syt1 to a Rab5-positive endocytic pathway. We conclude that the interaction between SV2A and Syt1 locks both molecules into surface nanoclusters, controlling their entry into recycling SVs.

neuroscience↗