Biology subjects

Goossens, V.

Publications and source records attributed to Goossens, V..

4 recordsLinked to original sources

bioRxiv2025

White matter microstructure changes across the lifespan: a meta-analysis of longitudinal diffusion MRI studies

BackgroundWhite matter in the human brain is known to play a critical role in facilitating communication between different brain regions. White matter microstructure is often quantified using fractional anisotropy (FA) derived from diffusion-weighted MRI and is often considered a key measure of neural efficiency that is positively associated with motor and cognitive functioning. While lifespan trajectories of FA have been well studied in cross-sectional designs, it remains less clear how FA changes longitudinally with age across the lifespan, and whether the rates of change are influenced by genetic variation. MethodsWe systematically reviewed the evidence of white matter changes, as measured by fractional anisotropy (FA) with diffusion magnetic resonance imaging longitudinally across the lifespan, and the genetic influences on this change. Searches were conducted in Medline, PsycInfo, and EMBASE up to August 2023 with terms related to DTI/FA and longitudinal/change. Following this, genetic-related search terms were applied to the results, and the search was broadened to include other measures of white matter change. Our systematic search resulted in 29 studies that met our criteria. In addition, 14 studies investigated genetic influences on FA change rates across the lifespan. A meta-regression using a thin-plate spline model was conducted to examine annual whole-brain FA change as a function of age. ResultsAcross childhood and adolescence, FA increased, and the rate of increase slowed into early adulthood. Between ages 20 and 35, changes in FA were not statistically significant. This was followed by a significant decline in FA between ages 36 and 50. The decreases plateaued between ages 51 and 61 and then continued at a slightly slower rate towards the upper end of the age range assessed (77 years). Average FA change per year relative to baseline assessment reached a maximum of +1.1% during development, and-0.6% per year, during ageing. Significant heritability was found for change in local but not global FA during development. During ageing, common variants in genes that have been related to increased risk for neuropsychiatric disorders (APOE, HTT, MAPT) were associated in some studies with accelerated local FA decreases over time. ConclusionsIn conclusion, there are changes in white matter microstructure within individuals across the lifespan, with increases during childhood, adolescence and early adulthood, followed by a period of relative stability during early to mid-adulthood, and subsequent gradual declines from midlife onwards. Evidence is emerging for genetic influences on white matter changes over time, shaping individual trajectories.

neuroscience↗

bioRxiv2022

Tau amyloid polymorphism is shaped by local structural propensities of its protein sequence

Different tauopathies are characterized by specific amyloid filament folds that are conserved between patients. Disease-specific tau filament folds probably reflect the specific pathological contexts leading to their formation including isoforms or post-translational modifications. Little is known, however, as to whether and how intrinsic conformational tendencies of the tau sequence itself contribute to its polymorphism. Using cryo-EM structure determination we find that a short amyloidogenic C-terminal peptide consisting of residues 350-362 of the tau repeat domain adopts the same polymorphic conformations in isolation as it does in the context of major disease-associated protofilament folds. Biophysical characterisation and molecular modelling show that the amyloid conformations adopted by this peptide constitute core structural motifs stabilizing distinct disease-associated tau filament folds. In accordance this segment also contributes to the efficient propagation of human AD tau seeds in tau reporter cells while it is irrelevant to heparin-induced recombinant seeds. Our findings suggest that tau 350-362 is key to the propagation of disease-associated tau polymorphs and that the conformational preferences of this segment predispose to the topological diversity observed in tau filament folds.

biophysics↗

bioRxiv2022

Systematic optimization of Cas12a base editors in wheat and maize using the ITER platform

The ever-increasing number of CRISPR components creates a significant burden when developing new genome engineering tools. Plant biotechnology in particular has few high-throughput options to perform iterative design-build-test-learn cycles when creating new gene-editing reagents. We have established ITER (Iterative Testing of Editing Reagents) based on arrayed protoplast transfections and high-content imaging, allowing one optimization cycle - from design to results- within three weeks. We validated ITER in wheat and maize protoplasts using Cas9 cytosine and adenine base editors. Given that previous LbCas12a-ABEs have low or no activity in plants, we used ITER to develop an optimized LbCas12a-ABE. We show that the sequential improvement of five components -NLS, crRNA, LbCas12a, adenine deaminase and linker- led to a remarkable increase in ABE activity from almost undetectable levels to 40% on an extrachromosomal GFP reporter. We confirmed the activity of LbCas12a-ABE at endogenous targets and in stable wheat transformants and leveraged these improvements to develop a highly mutagenic LbCas12a nuclease and LbCas12a-CBE. Our data show that ITER is a sensitive, versatile, and high-throughput platform that can be harnessed to accelerate the development of genome editing technologies in plants.

synthetic biology↗

bioRxiv2021

Mapping the sequence specificity of heterotypic amyloid interactions enables the identification of aggregation modifiers

Heterotypic amyloid interactions between related protein sequences have been observed in functional and disease amyloids. While sequence homology seems to favour heterotypic amyloid interactions, we have no systematic understanding of the structural rules determining such interactions nor whether they inhibit or facilitate amyloid assembly. Using structure-based thermodynamic calculations and extensive experimental validation, we performed a comprehensive exploration of the defining role of sequence promiscuity in amyloid interactions. Using this knowledge, we demonstrate, using tau as a model system, that predicted cross-interactions driven by sequence homology indeed can modify nucleation, fibril morphology, kinetic assembly and cellular spreading of aggregates. We also find that these heterotypic amyloid interactions can result in the mis-localisation of brain-expressed protein sequences with prevalent activities in neurodegenerative disorders. Our findings suggest a structural mechanism by which the proteomic background can modulate the aggregation propensity of amyloidogenic proteins and discuss how such sequence-specific proteostatic perturbations could contribute to the selective cellular susceptibility of amyloid disease progression.

biophysics↗