Biology subjects

Ness, D.

Publications and source records attributed to Ness, D..

3 recordsLinked to original sources

bioRxiv2023

Stealth liposomes encapsulating a potent ACAT1/SOAT1 inhibitor F12511: pharmacokinetic, biodistribution and toxicity studies in wild-type mice, and efficacy studies in triple transgenic Alzheimer Disease mice.

Cholesterol is essential to cellular function and is stored as cholesteryl esters (CEs). CEs biosynthesis is responsible by the enzymes acyl-CoA: cholesterol acyltransferase 1 and 2 (ACAT1 and ACAT2), with ACAT1 as the primary isoenzyme in most cells in humans. ACATs are targets for atherosclerosis therapies and may also be promising targets for treating Alzheimers Disease (AD). F12511 is a high-affinity ACAT1 inhibitor that has passed phase 1 safety tests for anti-atherosclerosis. Previously, we had developed a nanoparticle system to encapsulate a large concentration of F12511 into a stealth liposome (DSPE-PEG2000 with egg phosphatidylcholine). Here, we injected the nanoparticle encapsulated F12511 (nanoparticle F) intravenously (IV) to wild-type (WT) mice and performed HPLC/MS/MS analysis and ACAT enzyme activity measurement. The results demonstrated that F12511 was present within the mouse brain after a single IV but did not over-accumulate in the brain or other tissues after repeated IVs. Histological examination showed that F12511 did not cause overt neurological or systemic toxicity. We then showed that 2-week IV delivery of nanoparticle F to aging 3xTg AD mice ameliorated amyloidopathy, reduced hyperphosphorylated tau and non-phosphorylated tau, and reduced neuroinflammation. This work lays the foundation with nanoparticle F as a possible therapy for AD and other neurodegenerative diseases.

neuroscience↗

bioRxiv2023

Mutafy: A webserver to identify high quality mutant protein structures in the Protein Data Bank

Changes in the amino acid sequence of proteins resulting from nonsynonymous variants in the genome, can have significant effects on protein folding, stability, dynamics, and function, which may ultimately lead to diseases. The analysis of large sets of disease associated variants is a common approach for the study of pathogenic mechanisms. In-silico mutagenesis experiments based on wildtype structures of target proteins are a common approach to this aim, however these do not account for the effect of variants on folding and might not accurately reflect conformational changes. A growing number of experimentally solved protein structures harbouring disease-associated mutations, including single amino acid variants, are deposited in the worldwide Protein Data Bank (PDB). Nevertheless, identifying high-quality structures for specific missense variants of interest remains challenging due to the growing number of deposited protein structures in the PDB, and the lack of a dedicated interface and annotation system to search and retrieve mutant protein structures. As a result, mutant protein structures in the PDB are a powerful source of information which is largely underused. To address these shortcomings, we have developed Mutafy, a publicly available webserver to identify high quality mutant protein structures. Given input human genes, the webserver finds structures of the corresponding coded wildtype proteins and their available solved mutants, selects high quality structures, annotates them with information from biomedical databases to favour their interpretation and selection, and allows for the interactive exploration of the results and 3D visualisation. Mutafy is publicly available without requiring user registration at https://mutafy.rosalind.kcl.ac.uk.

bioinformatics↗

bioRxiv2022

Molecular dynamics analysis of Superoxide Dismutase 1 mutations suggests decoupling between mechanisms underlying ALS onset and progression

Mutations in the superoxide dismutase 1 (SOD1) gene are the second most common known cause of ALS. SOD1 variants express high phenotypic variability and over 200 have been reported in people with ALS. Investigating how different SOD1 variants affect the protein dynamics might help in understanding their pathogenic mechanism and explaining their heterogeneous clinical presentation. It was previously proposed that variants can be broadly classified in two groups, wild-type like (WTL) and metal binding region (MBR) variants, based on their structural location and biophysical properties. MBR variants are associated with a loss of SOD1 enzymatic activity. In this study we used molecular dynamics and large clinical datasets to characterise the differences in the structural and dynamic behaviour of WTL and MBR variants with respect to the wild-type SOD1, and how such differences influence the ALS clinical phenotype. Our study identified marked structural differences, some of which are observed in both variant groups, while others are group specific. Moreover, applying graph theory to a network representation of the proteins, we identified differences in the intramolecular contacts of the two classes of variants. Finally, collecting clinical data of approximately 500 SOD1 ALS patients carrying variants from both classes, we showed that the survival time of patients carrying an MBR variant is generally longer (~6 years median difference, p < 0.001) with respect to patients with a WTL variant. In conclusion, our study highlights key differences in the dynamic behaviour of the WTL and MBR SOD1 variants, and wild-type SOD1 at an atomic and molecular level. We identified interesting structural features that could be further investigated to explain the associated phenotypic variability. Our results support the hypothesis of a decoupling between mechanisms of onset and progression of SOD1 ALS, and an involvement of loss-of-function of SOD1 with the disease progression.

neuroscience↗