Biology subjects

Real, R.

Publications and source records attributed to Real, R..

8 recordsLinked to original sources

bioRxiv2026

Dimerisation and twist reversal of the Lewy fold in α-synuclein mutants with Parkinson's disease and dementia

Dominantly inherited missense and gene dosage mutations in SNCA, the -synuclein gene, cause familial forms of Parkinsons disease and dementia. Here we report the structures of -synuclein filaments from the brains of such individuals. Pathogenic mutations A53T and G51D in SNCA give rise to singlets and doublets of the Lewy fold with a left-handed helical twist in the absence of a peptide-like density for island A. By contrast, filaments from the non-pathogenic variant H50Q consist of singlets of the right-handed Lewy fold with a density for island A, like filaments of wild-type -synuclein. The structures of filaments from homozygous mice transgenic for human mutant A53T -synuclein (line M83) are unlike those from human brains. They are more similar to the multiple system atrophy folds than to the Lewy fold of Parkinsons disease, Parkinsons disease dementia and dementia with Lewy bodies

biophysics↗

bioRxiv2025

Longitudinal Proteomic Profiling Defines Robust Molecular Subtypes Underlying the Heterogeneity of Parkinson's Disease

Heterogeneity of Parkinsons disease (PD) pathology is a barrier to developing therapeutics and understanding progression and prognosis. High throughput proteomic measures can be used to better interpret PD pathophysiology and generate clusters to define disease subtypes. Identification of subtypes related to clinical phenotypes will help researchers understand PD progression. We analyzed longitudinal proteomic data from the Tracking Parkinsons Cohort, consisting of recent-onset PD patients across 72 UK sites. 794 patients were measured on the Somalogic platform (7596 proteins) for three time points. Weighted Gene Co-Expression Network Analysis (WGCNA) at each time point revealed consistent protein co-expression modules. Two modules were strongly preserved across all three time points and in validation in the Global Neurodegenerative Proteomics Consortia (GNPC) datasets. The brown module was enriched for metabolite pathways and the blue module with cellular signaling pathways and associated with quality of life scores. Conversely, the smaller red module had distinct cognitive function phenotypes and changed protein expression between visit time points. Using detailed characterization of proteomic clusters we have provided a comprehensive view of PD progression offering deeper insights into the conservation of proteomic expression, suggesting new module subsets and providing candidate target proteins for further study.

neuroscience↗

bioRxiv2025

17q21.31 locus regulates Parkinson's disease relevant pathways through KANSL1 activity

An inversion polymorphism at the 17q21.31 locus defines the H1 and H2 haplotypes, with the former linked to multiple neurodegenerative disorders, including an increased risk of Parkinsons disease (PD). Although the high linkage disequilibrium at this locus has made it difficult to decipher which gene(s) drive the PD association, there is increasing evidence to support the role of KANSL1 as a risk gene. KANSL1 has been shown to regulate the expression of some PD-associated genes and pathways, likely as part of the histone acetylating non-specific lethal (NSL) complex. Here for the first time, we studied the global effects of 17q21.31 haplotype variation using bulk and single-nuclear RNA-sequencing data from control and PD patient brain. We first analysed differential gene expression across haplotype groups, and then assessed the contribution of KANSL1 by comparing with the results of an siRNA knockdown in neuronal and glial human cell lines. We demonstrated that the PD risk-associated H1 haplotype downregulates autophagy, lysosomal and mitochondrial processes, all of which have already been implicated in PD aetiology. Furthermore, these effects were apparent in both neuronal and glial cell types, and in the case of the latter, appear to be associated with the modulation of innate and adaptive immune responses. Thus, we identify important links between NSL complex activity and PD pathophysiology that can be leveraged for novel therapeutic interventions.

neuroscience↗

bioRxiv2025

Molecular and cellular signatures differentiate Parkinson's disease from Parkinson's disease with dementia

Parkinsons disease (PD) affects millions of people worldwide, and up to 40% of these patients develop dementia, profoundly affecting their quality of life. Whether Parkinsons disease dementia (PDD) simply represents a late stage of PD or constitutes a distinct neurodegenerative process remains unresolved. To clarify this, we generated the largest single nuclear transcriptomic atlas of PD and PDD to date--almost one million nuclei derived from the anterior cingulate cortex and inferior parietal lobule of 64 post-mortem donors. By integrating these data with long-read RNA-seq, we found that the cellular compositions, biological pathways, and molecular profiles diverge substantially between PD and PDD, with limited overlap in differentially expressed genes and pathways. While PD was characterised by widespread upregulation of gene expression programs and robust regional signatures, PDD showed extensive pathway downregulation, loss of cortical regional identity, and significant shifts in transcript usage, including alterations in APP isoforms that may influence pathological amyloid beta accumulation. These findings reveal that PD and PDD represent fundamentally distinct disease states, offering important insights for understanding their underlying mechanisms and will guide the development of targeted therapies and more effective clinical trials.

neuroscience↗

bioRxiv2024

Altered neuronal network activity and connectivity in human Down Syndrome excitatory cortical neurons

Down syndrome (DS) is the most common genetic cause of intellectual disability, affecting one in 700 live births worldwide, and is caused by trisomy of the human chromosome 21 (Hsa21), yet the cellular and molecular mechanisms driving neuronal network dysfunction remain poorly understood. Here, we investigated whether trisomy 21 (TS21) alters the spontaneous synchronised activity of excitatory neuron networks, potentially contributing to the neurodevelopmental phenotypes of DS. By modelling human cortical development in vitro with TS21 and matched control human iPSCs from two DS donors, we investigated the impact of Hsa21 triplication on neural network activity and connectivity. Calcium imaging revealed an early and pronounced reduction in neuronal activity in TS21 cortical neurons, including a marked loss of synchronised bursting. These deficits persisted up to 80 days in vitro and for over 5 months in vivo following transplantation into the mouse forebrain, as shown by multiphoton calcium imaging through a cranial window. Viral trans-synaptic tracing identified significant reduction of neuronal connectivity in TS21 neuronal networks in vitro, suggesting that reduced network connectivity contributes to the dramatic reduction of synchronised bursting. Furthermore, TS21 neurons displayed significantly reduced expression of voltage-gated potassium channels, with single-neuron recordings confirming a reduction of hyperpolarization-activated currents. Together, these findings demonstrate long-lasting impairments in human cortical excitatory neuron network function associated with Trisomy 21.

neuroscience↗

bioRxiv2023

Potential climate change effects on the distribution of urban and sylvatic dengue and yellow fever vectors

Climate change may increase the risk of dengue and yellow fever transmission by urban and sylvatic mosquito vectors. Previous research primarily focused on Aedes aegypti and Aedes albopictus. However, these diseases involve a complex transmission cycle in which sylvatic vectors are also involved. Our aim was to analyse which mosquito species could contribute to the increased risk of transmission of these diseases due to climate change, and to identify where the risk increase could most likely occur. Using a biogeographical approach, we mapped areas where mosquito favourability could increase, decrease or remain stable in the near (2041-2060) and distant (2061-2080) future. Models predict dengue vectors expanding in West and Central Africa and in South-East Asia, reaching Borneo. Yellow fever vectors could spread in West and Central Africa and in the Amazon. In Europe, the models suggest a re-establishment of Ae. aegypti, while Ae. albopictus will continue to find new favourable areas. The results underline the need to focus more on vectors Ae. vittatus, Ae. luteocephalus and Ae. africanus in West and Central sub-Saharan Africa, especially Cameroon, Central Africa Republic, and northern Democratic Republic of Congo; and suggest the need for a protocol to prevent dengue and yellow fever that include surveillance of neglected sylvatic vectors.

ecology↗

bioRxiv2022

The IPDGC/GP2 Hackathon - an open science event for training in data science, genomics, and collaboration using Parkinson's disease data

BackgroundOpen science and collaboration are necessary to facilitate the advancement of Parkinsons disease (PD) research. Hackathons are collaborative events that bring together people with different skill sets and backgrounds to generate resources and creative solutions to problems. These events can be used as training and networking opportunities. ObjectiveTo coordinate a virtual hackathon to develop novel PD research tools. Methods49 early career scientists from 12 countries collaborated in a virtual 3-day hackathon event in May 2021, during which they built tools and pipelines with a focus on PD. Resources were created with the goal of helping scientists accelerate their own research by having access to the necessary code and tools. ResultsEach team was allocated one of nine different projects, each with a different goal. These included developing post-genome-wide association studies (GWAS) analysis pipelines, downstream analysis of genetic variation pipelines, and various visualization tools. ConclusionHackathons are a valuable approach to inspire creative thinking, supplement training in data science, and foster collaborative scientific relationships, which are foundational practices for early career researchers. The resources generated can be used to accelerate research on the genetics of PD.

genetics↗

bioRxiv2018

The psychometric validation of the Dutch version of the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) after Traumatic Brain Injury (TBI)

BackgroundTraumatic brain injury (TBI) is one of the most common neurological conditions. It can have wide-ranging physical, cognitive and psychosocial effects. Most people recover within weeks to months after the injury, but a substantial proportion are at risk of developing lasting post-concussion symptoms. The Rivermead Post-Concussion Syndrome Questionnaire (RPQ) is a short validated 16-items self-report instrument to evaluate post-concussive symptoms. The aim of this study was to test psychometrics characteristics of the current Dutch translation of the RPQ.\n\nMethodsTo determine the psychometric characteristics of the Dutch RPQ, 472 consecutive patients six months after they presented with a traumatic brain injury in seven medical centers in the Netherlands (N=397), and in two in Belgium (Flanders) (N=75) took part in the study which is part of the large prospective longitudinal observational CENTER-TBI-EU-study. Psychometric properties at six months post TBI, were assessed using exploratory and confirmatory factor analyses. Sensitivity was analyzed by comparing RPQ scores of patients after mild vs. moderate and severe TBI.\n\nFindingsThe Dutch version of RPQ proved good, showing excellent psychometric characteristics: high internal consistency (Cronbachs .93), and good construct validity, being sensitive to self-reported recovery status at six months post TBI. Moreover, data showed a good fit to the three dimensions structure of separate cognitive, emotional and somatic factors (Chi2=119; df=117; p=.4; CFI=.99; RMSEA=.006), reported earlier in the literature.\n\nDiscussionPsychometric characteristics of the Dutch version of RPQ proved excellent to good, and can the instrument therefore be applied for research purposes and in daily clinical practice.

scientific communication and education↗