Biology subjects

Lone, M. A.

Publications and source records attributed to Lone, M. A..

6 recordsLinked to original sources

bioRxiv2026

The COPI coatomer influences LDL receptor activity, hepatic lipid storage, and apoB secretion

BackgroundDecreased hepatic removal of low density lipoproteins (LDL) and increased apolipoprotein B (apoB) production cause hypercholesterolemia, a major causal risk factor of atherosclerotic cardiovascular disease (ASCVD). By a genome-wide siRNA screen, we previously identified subunits of the Coat protein I (COPI) complex to limit LDL uptake into Huh-7 hepatocarcinoma cells. MethodsThese findings were validated by targeted in vitro experiments as well as genetic association studies in humans and three mouse models with mutated or disrupted COPI genes. ResultsSilencing of COPA, COPB1, COPB2, ARCN1, COPG1, and COPZ1 in Huh-7 cells resulted in decreased uptake of LDL and aberrant glycosylation and altered cell surface abundance of the LDL receptor (LDLR) as well as increased apoB secretion and cellular lipid storage. Single nucleotide polymorphisms of ARCN1 were associated with lower ARCN1 expression and higher levels of LDL-cholesterol (LDL-C). Rare variants of COPA and COPG1 were enriched among patients with LDL-C > 5 mmol/L. Patients and mice carrying other rare immunopathogenic missense variants of COPA and COPG1 did not present with elevated plasma levels of LDL-C, while hepatic knockdown of murine Copg1 increased the concentrations of non-HDL-cholesterol in plasma and triglycerides in the liver. ConclusionsThe COPI coatomer regulates LDLR activity and apoB secretion as well as lipid content of liver cells. Loss of function of some variants of COPI genes are associated with higher LDL-C levels.

cell biology↗

bioRxiv2026

Sphingolipid remodelling in SPT-related neuropathies

Sphingolipid homeostasis is critical for neuronal structural and functional integrity in the central and peripheral nervous systems. The rate-limiting enzyme of this pathway, serine-palmitoyltransferase (SPT), establishes the metabolic entry point into sphingolipid biosynthesis. Mutations in the SPT subunits, SPTLC1 and SPTLC2 lead to contrasting disease phenotypes in patients, including amyotrophic lateral sclerosis (ALS) and hereditary sensory neuropathy (HSAN1). A third mixed sensory-motor phenotype is attributed to distinct mutation sets in SPTLC1 and SPTLC2. However, a direct comparison of the metabolic consequences of mutations spanning these disease conditions has not been performed. Here, we demonstrate that SPTLC1- and SPTLC2-ALS variants contribute to enhanced sphingolipid flux while the ceramide-mediated homeostatic control is impaired. In contrast, HSAN1-associated variants display altered substrate selectivity, shifting flux towards non-canonical 1-deoxysphingolipid (1-deoxySL) production but decreasing canonical synthesis. The variant associated with a mixed sensory-motor phenotype exhibit a third metabolic state with elevated 1-deoxySL formation and, in contrast to HSAN1-variants, increased canonical sphingolipid synthesis. Sphingolipid profiling reveals that ALS variants are characterized by preferential accumulation of dihydro- and intermediate chain sphingolipid species. Notably, the separation of lipid species between ALS and HSAN1 is robust, with canonical sphingolipids enriched in ALS variants, while long-chain 1-deoxySL dominate in HSAN1. The SPT-variants associated with mixed sensory and motor symptoms are associated with elevated levels of both types. The data support the view that segregated shifts in sphingolipid flux underlie divergence of clinical phenotypes in SPT-variants and offer guidance for therapeutic interventions. Importantly, therapeutic strategies must account for these metabolic configurations, as L-serine supplementation may benefit HSAN1 but exacerbate pathology in ALS and sensory-motor disease conditions.

neuroscience↗

bioRxiv2025

Dyslipidemic SPTLC3 Integrates Bile Acid-FXR Signaling with Sphingolipid Remodeling in MASLD

Molecular mechanisms driving metabolic disease pathogenesis remain poorly understood. Genetic and functional studies implicate SPTLC3 with dyslipidemia. SPTLC3 synthesizes atypical long-chain bases (LCB) precursors for sphingolipid production. We demonstrate significant SPTLC3 expression in human liver. ORMDL1-3 regulate SPTLC3 post-translationally in hepatic and non-hepatic cells. Independently, farnesoid X receptor (FXR) represses hepatic SPTLC3 transcription via a negative promoter element. In mice, high-fat diet (HFD) induced whereas bile acids normalized hepatic SPTLC3 transcription. SPTLC3 derived LCBs in plasma originate from the liver and are elevated in HFD-fed mice and in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Cross-species comparison revealed marked differences in LCB composition between mice and humans. Notably, omega-3-methylsphingosine (meC18SO) was significantly associated with MASLD in humans but undetectable in mice. In Huh7 cells, meC18SO enhanced complex II and IV activity, oxygen consumption, and mitochondrial ROS content. FXR-SPTLC3 axis and presented findings have potential implications for future translational research.

biochemistry↗

bioRxiv2025

Lack of motor defects and ALS-like neuropathology in heterozygous Sptlc1 Exon 2 deletion mice

Mutations in the human SPTLC1 gene have recently been linked to early onset amyotrophic lateral sclerosis (ALS), characterized by global atrophy, motor impairments, and symptoms such as tongue fasciculations. All known ALS-linked SPTLC1 mutations cluster within exon 2 and a specific variant, c.58G>T, results in exon 2 skipping. However, it is unclear how the exon 2 deletion affects SPTLC1 function in vivo and contributes to ALS pathogenesis. Leveraging the high genomic sequence similarity between mouse and human SPTLC1, we created a novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in the endogenous murine Sptlc1 locus. While heterozygous mice did not develop motor defects or ALS-like neuropathology, homozygous mutants died prematurely. These findings indicate that Sptlc1 {Delta}Exon2 heterozygous mice do not replicate the disease phenotype but provide valuable insights into SPTLC1 biology and serve as a useful resource for future mechanistic studies.

neuroscience↗

bioRxiv2023

Conformational dynamics of lipid transfer domains provide a general framework to decode their functional mechanism.

Lipid Transfer Proteins (LTPs) are key players in cellular homeostasis and regulation, as they coordinate the exchange of lipids between different cellular organelles. Despite their importance, our mechanistic understanding of how LTPs function at the molecular level is still in its infancy, mostly due to the large number of existing LTPs and to the low degree of conservation at the sequence and structural level. In this work, we use molecular simulations to characterize dynamical and mechanistic aspects of a representative dataset of Lipid Transport Domains (LTDs) of 12 LTPs that belong to 8 distinct families. We find that LTDs display common dynamical, rather than structural, features despite no sequence homology nor structural conservation. These dynamical features correlate with their mechanistic mode of action, allowing to interpret and design experimental strategies to further dissect their mechanism. Our findings indicate the existence of a conserved, fold-independent mechanism of lipid transfer across LTPs of various families and offer a general framework for understanding their functional mechanism.

biophysics↗

bioRxiv2022

SPTLC1 variants associated with childhood onset amyotrophic lateral sclerosis produce distinct sphingolipid signatures through impaired interaction with ORMDL proteins

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. Mutations in the SPTLC1 subunit of serine-palmitoyltransferase (SPT), which catalyzes the first step in the de novo synthesis of sphingolipids cause childhood-onset ALS. SPTLC1-ALS variants map to a transmembrane domain that interacts with ORMDL proteins, negative regulators of SPT activity. We show that ORMDL binding to the holoenzyme complex is impaired in cells expressing pathogenic SPTLC1-ALS alleles, resulting in increased sphingolipid synthesis and a distinct lipid signature. C-terminal SPTLC1 variants cause the peripheral sensory neuropathy HSAN1 due to the synthesis of 1-deoxysphingolipids (1-deoxySLs) that form when SPT metabolizes L-alanine instead of L-serine. Limiting L-serine availability in SPTLC1-ALS expressing cells increased 1-deoxySL and shifted the SL profile from an ALS to an HSAN1-like signature. This effect was corroborated in an SPTLC1-ALS pedigree in which the index patient uniquely presented with an HSAN1 phenotype, increased 1-deoxySL levels, and an L-serine deficiency. These data demonstrate how pathogenic variants in different domains of SPTLC1 give rise to distinct clinical presentations that are nonetheless modifiable by substrate availability.

biochemistry↗