Biology subjects

Leslie, K.

Publications and source records attributed to Leslie, K..

5 recordsLinked to original sources

bioRxiv2022

Effects of the investigational drug sodium phenylbutyrate-TUDCA (AMX0035) on the transcriptional and metabolic landscape of sporadic ALS fibroblasts

ALS is a rapidly progressive, fatal disorder caused by motor neuron degeneration, for which there is a great unmet therapeutic need. AMX0035, a combination of sodium phenylbutyrate (PB) and taurursodiol (TUDCA, Turso), has shown promising results in early ALS clinical trials, but its mechanisms of action remain to be elucidated. To obtain an unbiased landscape of AMX0035 effects we investigated the transcriptomic and metabolomic profiles of primary skin fibroblasts from sporadic ALS patients and healthy controls treated with PB, TUDCA, or PB-TUDCA combination (Combo). Combo changed many more genes and metabolites than either PB or TUDCA individually. Most changes were unique to Combo and affected the expression of genes involved in ALS-relevant pathways, such as nucleocytoplasmic transport, unfolded protein response, mitochondrial function, RNA metabolism, and innate immunity. Weighted gene coexpression network analysis showed that significant correlations between ALS gene expression modules and clinical parameters were abolished by Combo. This study is the first to explore the molecular effects of Combo in ALS patient-derived cells. It shows that Combo has a greater and distinct impact compared to the individual compounds and provides clues to drug targets and mechanisms of actions, which may underlie the benefits of this investigational drug combination.

neuroscience↗

bioRxiv2021

Genotype-phenotype correlation analysis and therapeutic development using a patient stem cell-derived disease model of Wolfram syndrome

Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant which is highly prevalent in the Ashkenazi-Jewish population. Clinical investigation indicates that subjects carrying the homozygous WFS1 c.1672C>T, p.R558C variant show mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C is more stable compared to the other known recessive pathogenic variants associated with Wolfram syndrome. Stem cell-derived islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulates genotype-related Wolfram phenotypes, which are milder than those of SC-islets with compound heterozygous WFS1 c.1672C>T (p.R558C), c.2654C>T (p.P885L). Enhancing residual WFS1 function by a combination treatment of chemical chaperones, sodium 4-phenylbutyrate (4-PBA) and tauroursodeoxycholic acid (TUDCA), mitigates detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and restored SC-islet function. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient stem cell-derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome. One sentence summaryDevelopment of personalized therapy for Wolfram syndrome using genetics and iPSC model.

genetics↗

bioRxiv2019

Juxta-membrane S-acylation of plant receptor-like kinases - fortuitous or functional?

S-acylation is a common post-translational modification of membrane protein cysteine residues with many regulatory roles. S-acylation adjacent to transmembrane domains has been described in the literature as affecting diverse protein properties including turnover, trafficking and microdomain partitioning. However, all of these data are derived from mammalian and yeast systems. Here we examine the role of S-acylation adjacent to the transmembrane domain of the plant pathogen perceiving receptor-like kinase FLS2. Surprisingly, S-acylation of FLS2 adjacent to the transmembrane domain is not required for either FLS2 trafficking or signalling function. Expanding this analysis to the wider plant receptor-like kinase superfamily we find that S-acylation adjacent to receptor-like kinase domains is common but poorly conserved between orthologues through evolution. This suggests that S-acylation of receptor-like kinases at this site is likely the result of chance mutation leading to cysteine occurrence. As transmembrane domains followed by cysteine residues are common motifs for S-acylation to occur, and many S-acyl transferases appear to have lax substrate specificity, we propose that many receptor-like kinases are fortuitously S-acylated once chance mutation has introduced a cysteine at this site. Interestingly some receptor-like kinases show conservation of S-acylation sites between orthologues suggesting that S-acylation has come to play a role and has been positively selected for during evolution. The most notable example of this is in the ERECTA-like family where S-acylation of ERECTA adjacent to the transmembrane domain occurs in all ERECTA orthologues but not in the parental ERECTA-like clade. This suggests that ERECTA S-acylation occurred when ERECTA emerged during the evolution of angiosperms and may have contributed to the neo-functionalisation of ERECTA from ERECTA-like proteins.

plant biology↗

bioRxiv2019

Reduced Plasma Ascorbic Acid Levels in Recipients of Myeloablative Conditioning & Hematopoietic Cell Transplantation

Hematopoietic cell transplantation (HCT) conditioned using myeloablative conditioning (MAC) is complicated by end organ injury due to endothelial dysfunction and graft versus host disease. Mucositis and oxidant injury results in micronutrient deficiency. Ascorbic acid (AA) levels were measured in 15 patients undergoing HCT conditioned with MAC (11 allogeneic and 4 autologous HCT). Ascorbate levels declined post conditioning to 27.3 ({+/-}14.1) by day 0 (p <0.05 compared with baseline), reaching a nadir level of 21.5 ({+/-}13.8) on day 14 (p <0.05) post-transplant. Patients undergoing allogeneic HCT continued to have low AA levels to day 60 post transplant, whereas recipients of autologous HCT recovered plasma AA levels to normal. The role of AA in maintaining endothelial function and hematopoietic as well as T cell recovery is provided, developing the rationale for repletion of vitamin C following HCT.

physiology↗

bioRxiv2018

Risk stratification of allogeneic stem cell recipients with respect to the potential for development of GVHD via their pre-transplant plasma lipid and metabolic signature

The clinical outcome of allogeneic hematopoietic stem cell transplantation (SCT) is strongly influenced from the complications arising during the post-transplant immune restoration and has been well studied and described. However, the metabolic status of the recipient pre-transplant also has the potential to influence this outcome and has never been studied before and has the potential to enable risk stratification with respect to the development of transplant associated complications such as graft vs. host disease (GVHD). In order to better understand this aspect of transplant related complications we investigated the pre-transplantation metabolic signature to assess the possibility of pre-transplant risk stratification. This pilot study was composed of 14 patients undergoing myeloablative conditioning followed by either HLA matched related, unrelated donor, or autologous stem cell transplantation. Blood samples were taken prior to transplant and the plasma was comprehensively characterized with respect to its lipidome and metabolome via LCMS and GCMS. The results indicated a significantly pro-inflammatory metabolic profile in patients who eventually developed Graft vs. Host Disease (GVHD). The data revealed 5 potential pre-transplant biomarkers (1-monopalmitin, diacylglycerol (DG) 38:5, DG 38:6, 2-aminobutyric acid, and fatty acid (FA) 20:1) that demonstrated high sensitivity and specificity towards predicting post-transplant GVHD development. The predictive model developed demonstrated an estimated predictive accuracy of risk stratification of 100%, with an Area under the Curve of the ROC of 0.995 with 100%. The likelihood ratio of 1-monopalmitin (infinity), DG 38:5 (6.0) and DG 38:6 (6.0) also demonstrated that a patient with a positive test result for these biomarkers pre-transplant will likely have very high odds of developing GVHD post-transplant. Collectively the data demonstrates the possibility of using pre-transplant metabolic signature for risk stratification of SCT recipients with respect to development of GVHD.

biochemistry↗