Abstract:Tauopathies are neurodegenerative diseases characterized by the pathological accumulation of microtubule-associated protein tau (MAPT) in the form of neurofibrillary tangles and paired helical filaments in neurons and glia, leading to brain cell death. These diseases include frontotemporal dementia (FTD) and Alzheimer’s disease (AD) and can be sporadic or inherited when caused by mutations in the MAPT gene. Despite an incredibly high socio-economic burden worldwide, there are still no effective disease-modifyi… Show more
“…Another locus of interest is a 1.5 Mb region of chromosome 17, namely 17q21 (Figure 5C). This region of the genome is well known in human genetics because it comprises a 1.5 Mb inversion polymorphism [30, 31] and the inversion alleles, actually haplotypes, have been associated with a wide variety of neurodegenerative disorders, including Progressive Supranuclear Palsy [32], corticobasal degeneration [33], frontotemporal dementia [34], and other tauopathies [35]. In this locus, altered MAPT is well known to affect risk for late-life neurodegenerative disorders.…”
In genome-wide association studies (GWAS), it has become commonplace to test millions of SNPs for phenotypic association. Gene-based testing can improve power to detect weak signal by reducing multiple testing and pooling signal strength. While such tests account for linkage disequilibrium (LD) structure of SNP alleles within each gene, current approaches do not capture LD of SNPs falling in different nearby genes, which can induce correlation of gene-based test statistics. We introduce an algorithm to account for this correlation. When a gene's test statistic is independent of others, it is assessed separately; when test statistics for nearby genes are strongly correlated, their SNPs are agglomerated and tested as a locus. To provide insight into SNPs and genes driving association within loci, we develop an interactive visualization tool to explore localized signal. We demonstrate our approach in the context of weakly powered GWAS for autism spectrum disorder, which is contrasted to more highly powered GWAS for schizophrenia and educational attainment. To increase power for these analyses, especially those for autism, we use adaptive p-value thresholding (AdaPT), guided by high-dimensional metadata modeled with gradient boosted trees, highlighting when and how it can be most useful.
Notably our workflow is based on summary statistics.
“…Another locus of interest is a 1.5 Mb region of chromosome 17, namely 17q21 (Figure 5C). This region of the genome is well known in human genetics because it comprises a 1.5 Mb inversion polymorphism [30, 31] and the inversion alleles, actually haplotypes, have been associated with a wide variety of neurodegenerative disorders, including Progressive Supranuclear Palsy [32], corticobasal degeneration [33], frontotemporal dementia [34], and other tauopathies [35]. In this locus, altered MAPT is well known to affect risk for late-life neurodegenerative disorders.…”
In genome-wide association studies (GWAS), it has become commonplace to test millions of SNPs for phenotypic association. Gene-based testing can improve power to detect weak signal by reducing multiple testing and pooling signal strength. While such tests account for linkage disequilibrium (LD) structure of SNP alleles within each gene, current approaches do not capture LD of SNPs falling in different nearby genes, which can induce correlation of gene-based test statistics. We introduce an algorithm to account for this correlation. When a gene's test statistic is independent of others, it is assessed separately; when test statistics for nearby genes are strongly correlated, their SNPs are agglomerated and tested as a locus. To provide insight into SNPs and genes driving association within loci, we develop an interactive visualization tool to explore localized signal. We demonstrate our approach in the context of weakly powered GWAS for autism spectrum disorder, which is contrasted to more highly powered GWAS for schizophrenia and educational attainment. To increase power for these analyses, especially those for autism, we use adaptive p-value thresholding (AdaPT), guided by high-dimensional metadata modeled with gradient boosted trees, highlighting when and how it can be most useful.
Notably our workflow is based on summary statistics.
“…Interestingly, different tau isoforms are associated with different forms of neurodegeneration, defining a subset of pathologies termed tauopathies. Hence, in Pick's Disease only 3R tau is found, while in corticobasal degeneration and in progressive supranuclear palsy only 4R tau isoforms are present in degenerative brains [157,163]. In other tauopathies both forms could be found, although with different stoichiometry, as in the case of the behavioral variant of frontotemporal dementia (with 3R isoform overrepresented compared to the 4R), primary progressive aphasia and primary age-related tauopathy.…”
Section: Tau and Tauopathiesmentioning
confidence: 99%
“…Furthermore, tau could be acetylated in some of the same residues targeted by ubiquitination. Thus, a model has been proposed [163] in which acetylation competes with ubiquitination, in turn avoiding the proteasomal system and favoring tau accumulation. Phosphorylation of tau is the most abundant PTM both in physiological and pathological contexts, with more than 80 phosphorylatable residues identified to date [176].…”
Section: Tau and Tauopathiesmentioning
confidence: 99%
“…Experiments conducted with hexanediol and by manipulating salt concentrations indicated that, similar to acetylation, phosphorylation of tau increases its propensity to form hydrophobic-driven LLPS and, conversely, inhibits electrostatic-driven LLPS [179]. Hyperphosphorylated tau has been observed as the major form of tau present in pathological aggregates [157,158,163,165,176]. Whereas some phospho-sites, such as Ser262, Ser356, and Ser396 [163,180], are found at basal levels and are likely to be key regulatory elements, others are exclusively detected in disease (e.g., Ser422, Ser396/Ser404 and Ser208 [163]).…”
Intrinsic disorder is a natural feature of polypeptide chains, resulting in the lack of a defined three-dimensional structure. Conformational changes in intrinsically disordered regions of a protein lead to unstable β-sheet enriched intermediates, which are stabilized by intermolecular interactions with other β-sheet enriched molecules, producing stable proteinaceous aggregates. Upon misfolding, several pathways may be undertaken depending on the composition of the amino acidic string and the surrounding environment, leading to different structures. Accumulating evidence is suggesting that the conformational state of a protein may initiate signalling pathways involved both in pathology and physiology. In this review, we will summarize the heterogeneity of structures that are produced from intrinsically disordered protein domains and highlight the routes that lead to the formation of physiological liquid droplets as well as pathogenic aggregates. The most common proteins found in aggregates in neurodegenerative diseases and their structural variability will be addressed. We will further evaluate the clinical relevance and future applications of the study of the structural heterogeneity of protein aggregates, which may aid the understanding of the phenotypic diversity observed in neurodegenerative disorders.
“…Hyperphosphorylation of intracellular Tau proteins was later recognized to be a major step in AD, as it leads to dysregulation of the neural cytoskeleton, cytologically characterized by neurofibrillary tangles (NFTs) ( Silva and Haggarty, 2020 ). In AD, such NFTs are first observed in the hippocampus and entorhinal cortex, causing local cerebral atrophy, before wider cerebral extension ( Congdon and Sigurdsson, 2018 ).…”
Section: Stress Depression and Alzheimer's Disease: A Bio-continuummentioning
The relationships between psychological stress and cognitive functions are still to be defined despite some recent progress. Clinically, we noticed that patients with Down syndrome (DS) may develop rapid neurocognitive decline and Alzheimer's disease (AD) earlier than expected, often shortly after a traumatic life event (bereavement over the leave of a primary caregiver, an assault, modification of lifestyle, or the loss of parents). Of course, individuals with DS are naturally prone to develop AD, given the triplication of chromosome 21. However, the relatively weak intensity of the stressful event and the rapid pace of cognitive decline after stress in these patients have to be noticed. It seems DS patients react to stress in a similar manner normal persons react to a very intense stress, and thereafter develop a state very much alike post-traumatic stress disorders. Unfortunately, only a few studies have studied stress-induced regression in patients with DS. Thus, we reviewed the biochemical events involved in psychological stress and found some possible links with cognitive impairment and AD. Interestingly, these links could probably be also applied to non-DS persons submitted to an intense stress. We believe these links should be further explored as a better understanding of the relationships between stress and cognition could help in many situations including individuals of the general population.
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