Biology subjects

Cleverley, K.

Publications and source records attributed to Cleverley, K..

7 recordsLinked to original sources

bioRxiv2025

Taf1 expression in mouse: novel transcripts and protein distribution

TATA-box binding protein associated factor 1 (TAF1) is the largest component of transcription factor IID (TFIID), a fundamental multiprotein complex for RNA polymerase II-mediated transcription. TAF1 is essential for promoter recognition, coactivator interaction, and normal development. Mutations in TAF1 cause developmental disorders and the lethal neurodegenerative disease X-linked dystonia-Parkinsonism (XDP). Our previous work suggested that this [~]170 kb gene has a more complex set of transcripts than currently catalogued. We therefore undertook a systematic assessment of Taf1 transcription in mouse, given its widespread use as a model organism and its high genetic homology with humans. Using targeted nanopore sequencing, we reveal extensive transcriptional diversity and differential abundance of Taf1 mRNAs across brain and body regions. We identify 19 novel transcript variants and multiple novel exons, and we predicted their protein domain architectures and modelled them using AlphaFold. Notably, we observed elevated RNA and protein expression in cerebellum compared to other brain regions. These findings substantially expand the transcriptional landscape of Taf1 and provide crucial insights to guide investigation of transcript-specific mechanisms in neurodevelopmental and neurodegenerative disorders, enabling the creation of more accurate disease models. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/674157v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1c31231org.highwire.dtl.DTLVardef@1df8a57org.highwire.dtl.DTLVardef@f35bd8org.highwire.dtl.DTLVardef@112c264_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

Reduction of Cystatin B results in increased cathepsin B activity in disomic but not Trisomy21 human cellular and mouse models

Down syndrome, resulting from trisomy of human chromosome 21, is a common form of chromosomal disorder that results in intellectual disability and altered risk of several medical conditions. Individuals with Down syndrome have a greatly increased risk of Alzheimers disease (DSAD), due to the presence of the APP gene on chromosome 21 that encodes the amyloid-{beta} precursor protein (APP). APP can be processed to generate amyloid-{beta}, which accumulates in plaques in the brains of people who have Alzheimers disease and is the upstream trigger of disease. Cathepsin B has potential roles in both APP processing and amyloid-{beta} degradation and has been suggested to contribute to amyloid-{beta} accumulation. An endogenous inhibitor of Cathepsin B, Cystatin B (CSTB), is encoded on chromosome 21. The abundance of this protein is increased in the brains of individuals with DSAD, which may be associated with a decrease in Cathepsin B activity compared to individuals who have Alzheimers disease in the general population. Whether targeting CSTB can modulate Cathepsin B activity in the context of trisomy of chromosome 21 is unclear. Here we test if reducing CSTB can alter Cathepsin B activity in a mouse and a cellular model of trisomy of chromosome 21. We find that reducing CSTB abundance increases Cathepsin B activity in disomic controls but not in the presence of trisomy of chromosome 21. These findings offer new insights into the role of CSTB in regulating Cathepsin B activity.

neuroscience↗

bioRxiv2023

Cathepsin B abundance, activity and microglial localisation in Alzheimer's disease-Down syndrome and early onset Alzheimer's disease; the role of elevated cystatin B

Cathepsin B is a cysteine protease that is implicated in multiple aspects of Alzheimers disease pathogenesis. The endogenous inhibitor of this enzyme, cystatin B (CSTB) is encoded on chromosome 21. Thus, individuals who have Down syndrome, a genetic condition caused by having an additional copy of chromosome 21, have an extra copy of an endogenous inhibitor of the enzyme. Individuals who have Down syndrome are also at significantly increased risk of developing early-onset Alzheimers disease (EOAD). The impact of the additional copy of cystatin B (CSTB) on Alzheimers disease development in people who have Down syndrome is not well understood. Here we compared the biology of cathepsin B and cystatin B (CSTB) in individuals who had Down syndrome and Alzheimers disease, with disomic individuals who had Alzheimers disease or were ageing healthily. We find that the activity of cathepsin B enzyme is decreased in the brain of people who had Down syndrome and Alzheimers disease compared with disomic individuals who had Alzheimers disease. This change occurs independently of an alteration in the abundance of the mature enzyme or the number of cathepsin B+ cells. We find that the abundance of cystatin B (CSTB) is significantly increased in the brains of individuals who have Down syndrome and Alzheimers disease compared to disomic individuals both with and without Alzheimers disease and we go on to investigate how this impacts enzyme activity in mouse and human cellular preclinical models of Down syndrome.

neuroscience↗

bioRxiv2022

Genetic mapping of APP and amyloid-β biology modulation by trisomy 21

Individuals who have Down syndrome frequently develop early onset Alzheimers disease, a neurodegenerative condition caused by the build-up of aggregated amyloid-{beta} and tau proteins in the brain. Amyloid-{beta} is produced by APP, a gene located on chromosome 21. People who have Down syndrome have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of Alzheimers disease in these individuals. Here we use a combination of next-generation mouse models of Down syndrome (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of amyloid-{beta} accumulation (AppNL-F) to determine how chromosome 21 genes other than APP modulate APP/amyloid-{beta} in the brain when in three copies. We demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate amyloid-{beta} accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene/genes causing this decrease in amyloid-{beta} accumulation and investigate the role of two lead candidate genes Dyrk1a and Bace2. Thus an additional copy of chromosome 21 genes, other than APP, can modulate APP/amyloid-{beta} in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD-DS compared to those who have familial AD caused by triplication of APP.

neuroscience↗

bioRxiv2021

Endosomal structure and APP biology are not altered in preclinical cellular models of Down syndrome

Individuals who have Down syndrome (trisomy 21) are at greatly increased risk of developing Alzheimers disease - dementia. Alzheimers disease is characterised by the accumulation in the brain of amyloid-{beta} plaques that are a product of amyloid precursor protein, encoded by the APP gene on chromosome 21. In Down syndrome the first site of amyloid-{beta} accumulation is within endosomes and changes to endosome biology occur early in disease. Here we determine if primary mouse embryonic fibroblasts isolated from two mouse models of Down syndrome can be used to study endosome and APP cell biology. We report that in these cellular models of Down syndrome endosome number, size and APP processing are not altered, likely because APP is not dosage sensitive in these models, despite three copies of App.

neuroscience↗

bioRxiv2020

The effects of CSTB duplication on APP/amyloid-β pathology and cathepsin activity in a mouse model

People with Down syndrome (DS), caused by trisomy of chromosome 21 have a greatly increased risk of developing Alzheimers disease (AD). This is in part because of triplication of a chromosome 21 gene, APP. This gene encodes amyloid precursor protein, which is cleaved to form amyloid-{beta} that accumulates in the brains of people who have AD. Recent experimental results demonstrate that a gene or genes on chromosome 21, other than APP, when triplicated significantly accelerate amyloid pathology in a transgenic mouse model of amyloid-{beta} deposition. Multiple lines of evidence indicate that cysteine cathepsin activity influences APP cleavage and amyloid-{beta} accumulation. Located on human chromosome 21 (Hsa21) is an endogenous inhibitor of cathepsin proteases, CYSTATIN B (CSTB) which is proposed to regulate cysteine cathepsin activity in vivo. Here we determined if three copies of the mouse gene Cstb is sufficient to modulate beta amyloid (A{beta}) accumulation and cathepsin activity in a transgenic APP mouse model. Duplication of Cstb resulted in an increase in transcriptional and translational levels of Cstb in the mouse cortex but had no effect on the deposition of insoluble A{beta} plaques or the levels of soluble or insoluble A{beta}42, A{beta}40, or A{beta}38 in 6-month old mice. In addition, the increased CSTB did not alter the activity of cathepsin B enzyme in the cortex of 3-month old mice. These results indicate that the single-gene duplication of Cstb is insufficient to elicit a disease-modifying phenotype in the dupCstb x tgAPP mice, underscoring the complexity of the genetic basis of AD-DS and the importance of multiple gene interactions in disease.

neuroscience↗

bioRxiv2020

Genetic dissection of Down syndrome-associated alterations in APP/amyloid-β biology using mouse models

Individuals who have Down syndrome (caused by trisomy of chromosome 21), have a greatly elevated risk of early-onset Alzheimers disease, in which amyloid-{beta} accumulates in the brain. Amyloid-{beta} is a product of the chromosome 21 gene APP (amyloid precursor protein) and the extra copy or dose of APP is thought to be the cause of this early-onset Alzheimers disease. However, other chromosome 21 genes likely modulate disease when in three-copies in people with Down syndrome. Here we show that an extra copy of chromosome 21 genes, other than APP, influences APP/A{beta} biology. We crossed Down syndrome mouse models with partial trisomies, to an APP transgenic model and found that extra copies of subgroups of chromosome 21 gene(s) modulate amyloid-{beta} aggregation and APP transgene-associated mortality, independently of changing amyloid precursor protein abundance. Thus, genes on chromosome 21, other than APP, likely modulate Alzheimers disease in people who have Down syndrome.

neuroscience↗