Biology subjects

Allinson, K.

Publications and source records attributed to Allinson, K..

5 recordsLinked to original sources

bioRxiv2025

Tau oligomers can occur in human brains within days of a single traumatic brain injury

Traumatic brain injury (TBI) is a major risk factor for Alzheimers disease (AD), yet the early molecular events linking the two remain unclear. Neurofibrillary tangles (NFTs), a hallmark of AD, are observed in individuals with a history of single or repetitive head injury. Animal studies show that tau oligomers, the toxic species preceding the NFTs, appear shortly after TBI, but corresponding human data are lacking. Here, we investigated tau changes in the brains of individuals who died shortly after TBI compared to those surviving long-term. We report abnormal tau oligomers in the brain of short-term survivors whereas NFTs were the main feature in long-term survivors. These findings support a model where TBI triggers early tau oligomers formation that spread through a prion-like mechanism, seeding tau pathology and contributing to late-onset AD. The novel identification of tau oligomers in acute TBI reveals potential early disease mechanisms and therapeutic targets for AD prevention. Importance statementBy revealing a potential early disease mechanism of Alzheimers disease (AD), this study represents a major breakthrough in our understanding, treatment and prevention of the disease. To our knowledge, this is the first report of tau oligomers in the brain of individuals suffering acute Traumatic Brain Injury (TBI). This is an important finding considering that TBI is a major risk factor of AD and tau oligomers are thought to be the most toxic species preceding tau pathology, a characteristic signature of AD. The identification of these early tau-related events after TBI provides insight into potential early AD mechanisms and offers a unique opportunity for early therapeutic intervention and prevention.

neuroscience↗

bioRxiv2024

Cancer-independent, second somatic NF1 mutation of normal tissues in neurofibromatosis type 1

INTRODUCTIONCancer predisposition syndromes mediated by recessive cancer genes generate tumours via somatic variants (second hits) in the unaffected allele. Second hits may or may not be sufficient for neoplastic transformation. Here, we performed whole genome and exome sequencing on 479 tissue biopsies from a child with neurofibromatosis type 1, a multi-system cancer-predisposing syndrome mediated by constitutive monoallelic NF1 inactivation. We identified multiple independent NF1 driver variants in histologically normal tissues, but not in 610 biopsies from two non-predisposed children. We corroborated this finding using targeted duplex sequencing, including a further nine adults with the same syndrome. Overall, truncating NF1 mutations were under positive selection in normal tissues from individuals with neurofibromatosis type 1. We demonstrate that normal tissues in neurofibromatosis type 1 commonly harbour second hits in NF1, the extent and pattern of which may underpin the syndromes cancer phenotype.

cancer biology↗

bioRxiv2020

Amplification, not spreading limits rate of tau aggregate accumulation in Alzheimer's disease

Both the replication of protein aggregates and their spreading throughout the brain are implicated in the progression of Alzheimers disease (AD). However, the rates of these processes are unknown and the identity of the rate-determining process in humans has therefore remained elusive. By bringing together chemical kinetics with measurements of tau seeds and aggregates across brain regions, we are able to quantify their replication rate in human brains. Remarkably, we obtain comparable rates in several different datasets, with 5 different methods of tau quantification, from seed amplification assays in vitro to tau PET studies in living patients. Our results suggest that the overall rate of accumulation of tau in neocortical regions is limited not by spreading between brain regions but by local replication, which doubles the number of seeds every ~5 years. Thus, we propose that limiting local replication constitutes the most promising strategy to control tau accumulation during AD.

biophysics↗

bioRxiv2019

Multi-site clonality analyses uncovers pervasive subclonal heterogeneity and branching evolution across melanoma metastases

Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naive patient and by leveraging the analytical power of multi-sample analyses, we reveal that metastatic cells may depart the primary tumour very early in the disease course and follow a branched pattern of evolution. Truncal UV-induced mutations that often swamp downstream analyses of heterogeneity, were found to be replaced by APOBEC-associated mutations in the branches of the evolutionary tree. Multi-sample analyses from a further 7 patients confirmed that branched evolution was pervasive, representing an important mode of melanoma dissemination. Our analyses illustrate that combining cancer cell fraction estimates across multiple metastases provides higher resolution phylogenetic reconstructions relative to single sample analyses and highlights the limitations of accurately inferring inter-tumoural heterogeneity from a single biopsy.

genomics↗

bioRxiv2017

An integrated genomic analysis of anaplastic meningioma identifies prognostic molecular signatures

Anaplastic meningioma is a rare and aggressive brain tumor characterised by intractable recurrences and dismal outcomes. Here, we present an integrated analysis of the whole genome, transcriptome and methylation profiles of primary and recurrent anaplastic meningioma. A key finding was the delineation of two distinct molecular subgroups that were associated with diametrically opposed survival outcomes. Relative to lower grade meningiomas, anaplastic tumors harbored frequent driver mutations in SWI/SNF complex genes, which were confined to the poor prognosis subgroup. Our analyses discern two biologically distinct variants of anaplastic meningioma with potential prognostic and therapeutic significance.

genomics↗