Biology subjects

Bergara, A.

Publications and source records attributed to Bergara, A..

6 recordsLinked to original sources

bioRxiv2026

Modulation of retroviral capsid assembly halts ARC-mediated TDP-43 intercellular spreading

Intercellular propagation of pathological TDP-43 drives the progression of ALS and FTD, yet the mechanisms enabling transmission remain elusive. Here, we demonstrate that Activity-regulated cytoskeleton associated protein (ARC/Arg3.1) is pathologically subverted to act as a retroviral-like capsid vehicle for TDP-43 spreading. In a Drosophila model, we reveal that massive Arc1 upregulation drives glia-to-neuron TDP-43 seeding, while its genetic ablation halts pathological transfer, improves motor function, and extends survival. In parallel human cellular models, stress-induced ARC colocalizes with TDP-43 to orchestrate its intercellular transmission. Guided by ARCs capsid architecture, we reproposed Lenacapavir, an FDA-approved HIV-1 capsid modulator, as a stable binder of ARC/Arg3.1 capsid interfaces. Lenacapavir treatment effectively blocks TDP-43 propagation in vitro and rescues disease phenotypes in vivo. Our findings establish ARC as a conserved vehicle for pathological protein transmission and deliver an immediately translatable pharmacological strategy to arrest disease progression in ALS and FTD.

neuroscience↗

bioRxiv2025

Computational Analysis of ELOVL6 Structure and Inhibition for Rational Drug Design

ELOVL6 is a key enzyme in long-chain fatty acid elongation, catalyzing the conversion of C16 fatty acids into C18 fatty acids. While its role in lipid metabolism is well established, recent studies have linked ELOVL6 to metabolic and neurodegenerative diseases, making it an attractive therapeutic target. However, the absence of a resolved crystal structure and limited mechanistic understanding of its inhibition pose significant challenges for drug discovery. In this study, we employ a multi-tiered computational approach, including structure prediction, molecular dynamics (MD) simulations, and free energy calculations, to investigate the structural basis of ELOVL6 function and inhibition. We identify the most thermodynamically favorable substrate binding pathway and characterize key conformational changes associated with ligand binding. By analyzing potential inhibitor binding pockets, we determine that known inhibitors preferentially target the active site, and we validate their binding affinities against experimental data. Additionally, by comparing ELOVL6 with homologous elongases, we pinpoint potentially key amino acid residues responsible for selectivity, providing insights that could guide structure-based drug design. Our findings establish a mechanistic framework for rational inhibitor development, offering a foundation for future efforts in optimizing ELOVL6-targeting therapeutics.

bioinformatics↗

bioRxiv2025

Real-time Visualization of Trigger Factor on Translating Ribosomes

Trigger Factor (TF) is an ATP-independent chaperone that assists in co-translational protein folding by associating with ribosomes to prevent aggregation. While its interaction with ribosomes has been described, real-time visualization of TF dynamics has remained elusive. Using high-speed atomic force microscopy, we imaged full 70S ribosomes under near-physiological conditions during translation. TF exhibited dynamic transitions between extended and compact conformations, forming both stable and transient contacts with ribosomal proteins uL23 and bL17 in ribosome-nascent chain complexes. Binding to non-translating ribosomes was not observed under these conditions. Molecular dynamics simulations of TF alone and in complex with ribosomal proteins supported the experimental observations. Our findings reveal the structural flexibility of TF and its selective association with active ribosomes. Our combination of experimental and computational approaches offers new insights into how TF dynamically engages ribosomes during translation to facilitate protein folding.

molecular biology↗

bioRxiv2022

Molecular dynamics simulations of the calmodulin-induced alpha-helix in the SK2 calcium-gated potassium ion channel

The family of small-conductance (SK) ion channels is composed of four members (SK1, SK2, SK3, and SK4) involved in neuron-firing regulation. The gating of these channels depends on the intracellular Ca2+ concentration, and their sensitivity to this ion is provided by calmodulin (CaM). This protein binds to a specific region in SK channels known as the calmodulin-binding domain (CaMBD), an event which is essential for their gating. While CaM-binding domains are typically disordered in the absence of CaM, the SK2 channel subtype displays a small pre-folded -helical region in its CaMBD even if CaM is not present. This small helix is known to turn into a full -helix upon CaM binding, although the molecular-level details for this conversion are not fully understood yet. In this work, we offer new insights on this physiologically relevant process by means of enhanced sampling, atomistic Hamiltonian replica exchange molecular dynamics simulations, providing a more detailed understanding of CaM binding to this target. Our results show that CaM is necessary for inducing a full -helix along the SK2 CaMBD through hydrophobic interactions with V426 and L427. However, it is also necessary that W431 does not compete for these interactions; the role of the small pre-folded -helix in the SK2 CaMBD would be to stabilize W431 so that this is the case.

biophysics↗

bioRxiv2022

Improved KCNQ2 gene missense variant interpretation with artificial intelligence

Advances in DNA sequencing technologies have revolutionized rare disease diagnosis, resulting in an increasing volume of available genomic data. Despite this wealth of information and improved procedures to combine data from various sources, identifying the pathogenic causal variants and distinguishing between severe and benign variants remains a key challenge. Mutations in the Kv7.2 voltage-gated potassium channel gene (KCNQ2) have been linked to different subtypes of epilepsies, such as benign familial neonatal epilepsy (BFNE) and epileptic encephalopathy (EE). To date, there is a wide variety of genome-wide computational tools aiming at predicting the pathogenicity of variants. However, previous reports suggest that these genome-wide tools have limited applicability to the KCNQ2 gene related diseases due to overestimation of deleterious mutations and failure to correctly identify benign variants, being, therefore, of limited use in clinical practice. In this work, we found that combining readily available features, such as AlphaFold structural information, Missense Tolerance Ratio (MTR) and other commonly used protein descriptors, provides foundations to build reliable gene-specific machine learning ensemble models. Here, we present a transferable methodology able to accurately predict the pathogenicity of KCNQ2 missense variants with unprecedented sensitivity and specificity scores above 90%.

pathology↗

bioRxiv2020

AN EPILEPSY-CAUSING MUTATION LEADS TO CO-TRANSLATIONAL MISFOLDING

Protein folding to the native state is particularly relevant in human diseases where inherited mutations lead to structural instability, aggregation and degradation. In general, the amino acid sequence carries all the necessary information for the native conformation, but the vectorial nature of translation can determine the folding outcome. Calmodulin (CaM) recognizes the properly folded Calcium Responsive Domain (CRD) of Kv7.2 channels. Within the IQ motif (helix A), the W344R mutation found in epileptic patients has negligible consequences for the structure of the complex as monitored by multiple in vitro binding assays and molecular dynamic computations. In silico studies revealed two orientations of the side chain, which are differentially populated by WT and W344R variants. Binding to CaM is impaired when the mutated protein is produced in cellulo but not in vitro, suggesting that this mutation impedes proper folding during translation within the cell by forcing the nascent chain to follow a folding route that leads to a non-native configuration, and thereby generating non-functional ion channels that fail to traffic to proper neuronal compartments.

biophysics↗