Biology subjects

Ruiz-Perez, L.

Publications and source records attributed to Ruiz-Perez, L..

6 recordsLinked to original sources

bioRxiv2024

Multivalent Targeting of Blood-Brain Barrier LRP1 for Neurovascular Recovery Therapy for Alzheimer s Disease

The blood-brain barrier (BBB) is a highly selective permeability barrier that safeguards the central nervous system (CNS) from potentially harmful substances while regulating the transport of essential molecules. Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimers disease (AD), contributing to the accumulation of amyloid-{beta} (A{beta}) plaques. We propose an AD therapeutic strategy targeting the BBB low-density lipoprotein receptor-related protein 1 (LRP1). We show that a multivalent scaffold with LRP1-specific peptide modulates the A{beta} transport at the BBB. We show via detailed experimentation on AD model mice that this intervention markedly reduces A{beta} deposits and prevents cognitive decline. This study marks a new approach to drug design, combining multivalent targeting with the regulation of membrane trafficking through advanced molecular engineering. Crucially, the therapeutic effects emerge from the multivalent nature of our proposed system. Furthermore, our findings underscore the paramount significance of the BBB in AD pathogenesis, particularly emphasizing the critical role of LRP1-mediated A{beta} clearance in mitigating disease progression.

neuroscience↗

bioRxiv2024

Imaging Abeta aggregation by liquid-phase transmission electron microscopy

The amyloid beta peptide (A{beta}) readily aggregates into amyloid fibrils. This process has been the subject of intense investigations since it is associated with Alzheimers disease. However, it has been highly challenging to observe the microscopic steps in the aggregation reaction directly and to characterize the oligomeric assemblies formed as intermediates. To achieve this goal, we apply liquid-phase transmission electron microscopy (LTEM) in combination with all-atom molecular dynamics simulations. Our results offer an initial visualization of the dynamics of A{beta} oligomers, the formation of A{beta} protofibrils, and the presence of A{beta} oligomers on the surface of A{beta} fibrils. This work illustrates how the application of LTEM to the study of protein aggregation in solution enables the imaging of key molecular events in the aggregation process of A{beta}.

biophysics↗

bioRxiv2023

SimpliPyTEM: An open-source Python library and app to simplify Transmission Electron Microscopy and in situ-TEM image analysis.

Introducing SimpliPyTEM, a Python library and accompanying GUI that simplifies the post-acquisition evaluation of transmission electron microscopy (TEM) images, helping streamline the workflow. After an imaging session, a folder of image and/or video files, typically containing low contrast and large file size 32-bit images, can be quickly processed via SimpliPyTEM into high-quality, high-contrast .jpg images with suitably sized scale-bars. The app can also generate HTML or PDF files containing the processed images for easy viewing and sharing. Additionally, SimpliPyTEM has a specific focus on in situ TEM videos, an emerging field of EM, allowing for fast data processing into preview movies, averages, image series, or motion corrected averages using MotionCor2. The accompanying Python library offers many standard image processing methods, all simplified to a single command, plus a module to analyse particle morphology and population. This latter application is particularly useful for life sciences investigations. User-friendly tutorials and clear documentation are included to help guide users through the processing and analysis. We invite the EM community to contribute to and further develop this open-source package.

biophysics↗

bioRxiv2023

Kinetic stabilization of translation-repression condensates by a neuron-specific microexon

The inclusion of microexons by alternative splicing is frequent in neuronal proteins. The roles of these sequences are in most cases unknown, but changes in their degree of inclusion are associated with neurodevelopmental diseases. We recently found that the decreased inclusion of a 24-nucleotide neuron-specific microexon in CPEB4, an RNA-binding protein that regulates translation through cytoplasmic changes in poly(A) tail length, is linked to idiopathic autism spectrum disorder (ASD). Why this microexon is required and how small changes in its degree of inclusion generate a dominant-negative effect on the expression of ASD-linked genes is not clear. Here we show that neuronal CPEB4 forms condensates that dissolve upon depolarization, a transition associated with a switch from translational repression to activation. Heterotypic intermolecular interactions between the microexon and a cluster of histidine residues kinetically stabilize the condensates by competing with homotypic interactions between clusters, that otherwise lead to the irreversible aggregation of CPEB4. We conclude that the microexon is required in neuronal CPEB4 to preserve the reversible regulation of CPEB4-mediated gene expression in response to neuronal stimulation.

biophysics↗

bioRxiv2021

Imaging protein conformational space in liquid water

Withdrawal StatementThe authors have withdrawn their manuscript owing to a mistake in one of the proteins used for the data used to generate Fig.1, where we believed we used the apoferritin but instead used the ferritin proteins. Therefore, the authors do not wish this work to be cited as a reference for the project. If you have any questions, please get in touch with the corresponding author.

biophysics↗

bioRxiv2018

An Organometallic Ir(III) Molecular Probe for Imaging Microtubules in Fluorescence and Electron Microscopy

We report a versatile cyclometalated Iridium (III) complex probe that achieves synchronous fluorescence-electron microscopy correlation to reveal microtubule ultrastructure in cells. The selective insertion of probe between repeated and {beta} units of microtubule triggers remarkable fluorescent enhancement, and high TEM contrast due to the presence of heavy Ir ions. The highly photostable probe allows live cell imaging of tubulin localization and motion during cell division with an resolution of 20 nm, and under TEM imaging reveals the {beta} unit interspace of 45[A] of microtubule in cells.

cell biology↗