Biology subjects

Ambaw, Y. A.

Publications and source records attributed to Ambaw, Y. A..

7 recordsLinked to original sources

bioRxiv2026

A membrane homeostatic response to lipid overload coordinates fatty acid metabolism

Excess fatty acids can disrupt membrane and organelle function. Cells buffer fatty acid toxicity by synthesizing and storing triglycerides (TGs) in lipid droplets, but their capacity for TG storage is limited. Here, we impaired TG synthesis in hepatocytes and identified adaptive pathways that restore homeostasis during lipid overload. Transcription responds by activating fatty acid oxidation through peroxisome proliferator-activated receptors, and by suppressing synthesis of new, unsaturated fatty acids through sterol regulatory element-binding protein 1 (SREBP1). Mechanistically, SREBP1 appears to respond to changes in ER membrane fluidity. These findings reveal a homeostatic system monitoring and maintaining the ER membrane, coordinating fatty acid synthesis and oxidation, a finding with broad implications for understanding lipid physiology and developing TG synthesis inhibitors for treating fatty liver disease.

cell biology↗

bioRxiv2025

Proteome Landscapes Decode Organelle Vulnerabilities in cortical and dopaminergic-like induced neurons Across Lysosomal Storage Disorders

Lysosomes maintain cellular homeostasis by degrading proteins delivered via endocytosis and autophagy, and by recycling building blocks for organelle biogenesis. Lysosomal Storage Disorders (LSDs) comprise a group of diseases affecting diverse lysosomal functions. To facilitate molecular phenotyping across diverse LSD gene classes, we are developing a library of human embryonic stem cells engineered to lack individual LSD genes as a resource for the field. Here, we report our initial stem cell toolkit lacking one of 23 LSD genes, including the majority of genes associated with sphingolipidoses and neuronal ceroid lipofuscinoses, and its use in the generation of a proteomic resource for induced cortical-like and midbrain dopaminergic-like neurons In-depth abundance and correlation profiling across organelles and sub-organelle components revealed potential vulnerabilities that reflect distinct patterns of proteome alterations across both genotypes and neuronal cell types. We characterize alterations in the mitochondrial proteome associated with GBA1 and ASAH1 deficiency and identify synaptic and mitochondrial defects in ASAH1-/- induced neurons that correlate with defects in neuronal firing rates. Moreover, we developed an informatic pipeline for proteome-wide identification of individual protein interactions and protein complexes that may be disrupted as a result of LSD gene deficiency. Finally, we visualized structural alterations of ASAH1-deficient endolysosomes in situ using cryo-electron tomography, revealing swollen organelles that were largely devoid of dense internal membranes characteristic of wild-type cells, but containing numerous intralumenal vesicle compartments. This toolkit and associated proteomic landscapes provide a resource for defining molecular signatures associated with LSD gene dysfunction and organelle vulnerability.

cell biology↗

bioRxiv2025

Plasma lipidome dysregulation in frontotemporal dementia reveals shared, genotype-specific, and severity-linked alterations

Developing new treatment strategies for frontotemporal dementia (FTD) and other forms of neurodegeneration requires biomarkers to monitor disease progression. Dysregulated brain lipid metabolism, particularly sphingolipids enriched in the nervous system, is a key feature of neurodegeneration. However, plasma lipids have been investigated less for their potential as biomarkers than brain imaging and serum proteins. Here we examined the plasma lipidomes of a cohort of heterozygous carriers of gene variants associated with autosomal dominant familial FTD (including GRN, C9orf72, and MAPT loci), comparing them with aged-matched controls. In general, FTD subjects exhibited increases in plasma levels of specific species of gangliosides (GM3(d18:1_16:0), GM3(d18:1_18:0), and GM3(d18:1_24:1)) and ceramide (Cer(d18:1_23:0)) and selected polyunsaturated triacylglycerols (TG). Other species of ceramides (Cer(d18:0_22:0)), phosphatidylethanolamine (PE(18:0_24:0)), and sphingomyelin (SM(38:0)) were reduced in plasma of FTD subjects. Levels of glucosylsphingosine (GlcSph(d18:1)) were elevated specifically in GRN carriers, SM(34:1) was reduced in C9orf72 carriers, and TG(16:0_18:1_20:3)) were decreased in MAPT variant carriers. Notably, the ganglioside GM3(d18:1_16:0) was consistently elevated across all FTD genetic subtypes. Furthermore, the levels of these lipids correlated with disease severity in FTD patients. Our findings suggest that specific plasma lipid changes, notably several sphingolipids, may be useful biomarkers for FTD disease or progression.

systems biology↗

bioRxiv2025

DHRS7 Integrates NADP+/NADPH Redox Sensing with Inflammatory Lipid Signalling via the Oxoeicosanoid Pathway

During the innate immune response at epithelial wound sites, oxidative stress acts microbicidal and--mechanistically less well understood--as an immune and resilience signal. The reversible sulfhydryl (SH) oxidation of kinases, phosphatases, and transcription factors constitute the perhaps best-known redox signalling paradigm, whereas mechanisms that transduce metabolic redox cues, such as redox cofactor balance, remain little explored. Here, using mammalian cells, microsomes, and live zebrafish, we identify DHRS7, a short-chain fatty acid dehydrogenase/reductase (SDR), as conserved, 5-hydroxyeicosanoid dehydrogenase (5-HEDH). Under oxidative stress, DHRS7 consumes NADP+ to convert arachidonic acid (AA)-derived 5(S)-HETE into the inflammatory lipid 5-KETE, which activates leukocyte chemotaxis via the OXER1 receptor. While Dhrs7 acts as a NADPH-dependent 5-KETE sink in unstressed, healthy tissue, it promotes rapid, 5-KETE dependent leukocytic inflammation in wounded zebrafish skin. Thus, DHRS7 epitomizes an underappreciated mode of redox signalling--beyond classic SH oxidation--that leverages NADPH metabolism to generate or quench a paracrine lipid signal. Metabolic redox sensors like DHRS7 might be promising therapeutic targets in diseases characterized by disturbed redox balance.

immunology↗

bioRxiv2024

Carboxy-terminal blockade of sortilin binding enhances progranulin gene therapy, a potential treatment for frontotemporal dementia

Frontotemporal dementia is commonly caused by loss-of-function mutations in the progranulin gene. Potential therapies for this disorder have entered clinical trials, including progranulin gene therapy and drugs that reduce progranulin interactions with sortilin. Both approaches ameliorate functional and pathological abnormalities in mouse models of progranulin insufficiency. Here we investigated whether modifying the progranulin carboxy terminus to block sortilin interactions would improve the efficacy of progranulin gene therapy. We compared the effects of treating progranulin-deficient mice with gene therapy vectors expressing progranulin with intact sortilin interactions, progranulin with the carboxy terminus blocked to reduce sortilin interactions, or GFP control. We found that expressing carboxy-terminally blocked progranulin generated higher levels of progranulin both at the injection site and in more distant regions. Carboxy-terminally blocked progranulin was also more effective at ameliorating microgliosis, microglial lipofuscinosis, and lipid abnormalities including ganglioside accumulation and loss of bis(monoacylglycero)phosphate lipids. Finally, only carboxy-terminally blocked progranulin reduced plasma neurofilament light chain, a biomarker of neurodegeneration, in progranulin-deficient mice. These results demonstrate that modifying the progranulin cargo to block sortilin interactions may be important for increasing the effectiveness of progranulin gene therapy. One-sentence SummaryThe effectiveness of progranulin gene therapy in models of FTD is improved by blocking the proteins carboxy terminus, which prevents sortilin binding

neuroscience↗

bioRxiv2022

Lipodystrophy can be uncoupled from detrimental metabolic consequences

Triglycerides (TG) in adipocytes provide the major stores of metabolic energy in the body. Optimal amounts of TG stores are desirable as insufficient capacity to store TG, as in lipodystrophy, or exceeding the capacity for storage, as in obesity, results in metabolic disease. We hypothesized that mice lacking TG storage in adipocytes would result in excess TG storage in cell types other than adipocytes and severe lipotoxicity accompanied by metabolic disease. To test this hypothesis, we selectively deleted both TG-synthesis enzymes, DGAT1 and DGAT2, in adipocytes (ADGAT DKO mice). As expected with depleted energy stores, ADGAT DKO mice did not tolerate fasting well and, with prolonged fasting, entered torpor. However, ADGAT DKO mice were unexpectedly otherwise metabolically healthy and did not accumulate TGs ectopically or develop associated metabolic perturbations, even when fed a high-fat diet. The favorable metabolic phenotype resulted from activation of energy expenditure, in part via BAT activation and beiging of white adipose tissue. Thus, the ADGAT DKO mice provide a fascinating new model to study the coupling of metabolic energy storage to energy expenditure.

physiology↗

bioRxiv2021

Progranulin deficiency results in reduced bis(monoacylglycero)phosphate (BMP) levels and gangliosidosis

Homozygous mutations of granulin precursor (GRN) lead to neuronal ceroid lipofuscinosis1, a severe neurodevelopmental disease, in humans and neuroinflammation in mice2. Haploinsufficiency of GRN almost invariably causes frontotemporal dementia (FTD)3,4. The GRN locus produces progranulin (PGRN), a lysosomal precursor protein that is cleaved to granulin peptides5,6. Despite intensive investigation, the function of granulins and the reason why their absence causes neurodegeneration remain unclear. Here, we investigated PGRN function in lipid degradation, a major function of lysosomes. We show that PGRN-knockout human cells, PGRN-deficient murine brain, and frontal lobes of human brains from patients with GRN mutation-related FTD have increased levels of gangliosides, highly abundant sialic acid-containing glycosphingolipids (GSL) that are degraded in lysosomes. Probing how PGRN deficiency causes these changes, we found normal levels and activities of enzymes that catabolize gangliosides. However, levels of bis(monoacylglycero)phosphate (BMP), a lysosomal lipid required for ganglioside catabolism7, were markedly reduced in PGRN-deficient cells and patient brain tissues. These data indicate that granulins are required to maintain BMP levels, which regulate ganglioside catabolism, and that PGRN deficiency in lysosomes leads to gangliosidosis. This aberrant accumulation of gangliosides may contribute to neuroinflammation and neurodegeneration susceptibility.

cell biology↗