Single-Nucleus Chromatin Accessibility Profiling Highlights Distinct Astrocyte Signatures in Progressive Supranuclear Palsy and Corticobasal Degeneration
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PROVIDER: PRJEB54978 | ENA |
REPOSITORIES: ENA
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Project description:Genome wide Methylation profiling of DNA extracted from post-mortem forebrains of PSP patients (n=94) and of controls (n=72). The Illumina Infinium HumanMethylation450 BeadChip was used representing 485,000 potentially methylated CpG sites throughout the genome.
2018-12-01 | GSE75704 | GEO
Project description:Progressive supranuclear palsy (PSP) is a neurodegenerative parkinsonian disorder. This study using CSF samples of PSP patients is a follow-up study to discover biomarkers related to the previous PSP brain results. This study is the first-ever attempt at an in-depth global proteomic study using more than 100 CSF samples for PSP study. In this study, we used the 11-plex isobaric tandem-mass-tag (TMT) technology for more accurate and sensitive quantification of CSF proteins and analyzed them using Orbitrap Fusion Lumos mass spectrometry on 40 PSP and 40 PD patients as well as 40 HC individuals CSF samples for the discovery experiment. These candidate biomarkers discovered in this study will pave the way for the development of reliable PSP biomarkers.
2025-05-06 | PXD041417 | Pride
Project description:Progressive supranuclear palsy (PSP) is a neurodegenerative disorder clinically characterized by progressive postural instability, supranuclear gaze palsy, parkinsonism, and cognitive decline caused by degeneration in specific areas of the brain including globus pallidus (GP), substantia nigra, and subthalamic nucleus. However, the pathogenetic mechanism of PSP remains unclear to date. Unbiased global proteome analysis of patients’ brain samples is an important step toward understanding PSP pathogenesis, as proteins serve as workhorses and building blocks of the cell. In this study, we conducted unbiased mass spectrometry-based global proteome analysis of GP samples from 15 PSP patients, 15 Parkinson disease (PD) patients, and 15 healthy control (HC) individuals. To analyze 45 samples, we conducted 5 batches of 11-plex isobaric tandem mass tag (TMT)-based multiplexing experiments, identifying 10,231 proteins. The gene set enrichment analysis results showed that the PD pathway was the most highly enriched, followed by pathways for oxidative phosphorylation, Alzheimer disease, Huntington disease, and non-alcoholic fatty liver disease (NAFLD) when PSP was compared to HC or PD. Most of the proteins enriched in the gene set enrichment analysis were mitochondrial proteins such as cytochrome c oxidase, NADH dehydrogenase, acyl carrier protein, succinate dehydrogenase, ADP/ATP translocase, cytochrome b-c1 complex, and/or ATP synthase. Strikingly, all of the enriched mitochondrial proteins in the PD pathway were downregulated in PSP compared to both HC and PD. The subsequent Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) protein-protein interaction (PPI) analysis and the weighted gene co-expression network analysis (WGCNA) further supported that the mitochondrial proteins were the most highly enriched in PSP. This is the first global proteome analysis of human GP from PSP patients, and this study paves the way to understanding the pathogenesis mechanism of PSP.
2022-12-08 | PXD031648 | Pride
Project description:Tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) exhibit characteristic neuronal and glial inclusions of hyperphosphorylated Tau (pTau). Although the astrocytic pTau phenotype upon neuropathological examination is the most guiding feature in distinguishing both diseases, regulatory mechanisms controlling their transitions into disease-specific states are poorly understood to date. Here, we provide accessible chromatin data of more than 45,000 single nuclei isolated from the frontal cortex of PSP, CBD, and control individuals. We found a strong association of disease-relevant molecular changes with astrocytes and demonstrate that tauopathy-relevant genetic risk variants are tightly linked to astrocytic chromatin accessibility profiles in the brains of PSP and CBD patients. Unlike the established pathogenesis in the secondary tauopathy Alzheimer disease, microglial alterations were relatively sparse. Transcription factor (TF) motif enrichments in pseudotime as well as modeling of the astrocytic TF interplay suggested a common pTau signature for CBD and PSP that is reminiscent of an inflammatory immediate-early response. Nonetheless, machine learning models also predicted discriminatory features, and we observed marked differences in molecular entities related to protein homeostasis between both diseases. Predicted TF involvement was supported by immunofluorescence analyses in postmortem brain tissue for their highly correlated target genes. Collectively, our data expand the current knowledge on risk gene involvement (e.g., MAPT, MAPK8, and NFE2L2) and molecular pathways leading to the phenotypic changes associated with CBD and PSP.
| S-EPMC9468099 | biostudies-literature
Project description:Deciphering the pathophysiological mechanisms that lead from the alteration of human Tau biology to neuronal death in tauopathies including Alzheimer's disease (AD), fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick's disease (PiD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) depends notably on the identification of Tau cellular partners and a better understanding of Tau functions. In this aim, we performed gene expression profiling to identify upregulated and downregulated genes in response to ectopic induced expression for 3 days of human Tau0N4RWT protein in Drosophila primary neuronal cultures from Elav-GAL4GS larval brains.
2020-02-11 | E-MTAB-8712 | biostudies-arrayexpress
Project description:Progressive supranuclear palsy (PSP) is a late-onset neurodegenerative disease defined pathologically by the presence of insoluble phosphorylated-Tau (p-Tau) in neurons and glia. Identifying co-aggregating proteins within p-Tau inclusions reveals important insights into processes affected by the aggregation of Tau. Here, we used an unbiased proteomic approach, which combines antibody-mediated proximity-detection of co-aggregated proteins together with mass spectrometry. Biotinylation by antibody recognition (BAR) is a recently developed method, by which a primary antibody recognises the target of interest in fixed samples. A secondary antibody conjugated to horseradish peroxidase (HRP) recognises the primary antibody, and with the addition of biotin phenol and hydrogen peroxide, facilitates biotinylation of proteins in close proximity. Biotinylated proteins are then biochemically isolated and identified using mass spectrometry (MS). Using this workflow, we characterised the aggresome of p-Tau in PSP cases, identifying >80% of previously identified interaction partners of Tau as well as known modifiers of Tau aggregation. Our data also identified confidently assigned phosphorylation sites that have previously been reported on p-Tau. Together these data validate our proof-of-concept approach to rapidly identify proteins in proximity to p-Tau from post-mortem tissue whilst also isolating novel protein components that have not been previously associated with p-Tau.
2023-02-27 | PXD028770 | Pride
Project description:IntroductionThere is growing interest in using patient-reported outcomes as end points in clinical trials, such as the progressive supranuclear palsy quality of life (PSP-QoL) scale. However, this tool has not been widely validated and its correlation with validated motor scales has not been explored. To evaluate the potential utility of using PSP-QoL as an outcome, it is important to examine its relationship with a standard scale used to evaluate neurologic parameters, such as the PSP Rating Scale.MethodsPSP-QoL and PSP Rating Scale scores were gathered from 60 clinically diagnosed PSP patients, including patients with Richardson syndrome PSP (PSP-RS, n = 43) and those with non-RS PSP variants (n = 17). Linear regression analysis adjusted for age, sex, and disease duration was used to evaluate the cross-sectional relationship between the total and subscale scores of the 2 instruments.ResultsAmong 60 PSP patients, there was a significant correlation between total PSP-QoL and PSP Rating Scale scores. The physical and mentation subscales of each instrument also demonstrated significant correlations. Comparisons among PSP subtypes indicated that worsening PSP-QoL Total and Physical subscale scores correlated with worsening PSP Rating Scale gait subscale scores more strongly for the non-RS PSP variants than for PSP-RS.DiscussionThere is a significant association between the total scores and many of the subscale scores of the PSP-QoL and the PSP Rating Scale. Additionally, the relationship between these measures may differ for PSP-RS and non-RS variants. These findings suggest that the PSP-QoL may be useful in clinical trials as a patient-reported outcome measure. Large prospective multicenter studies utilizing the PSP-QoL are necessary to examine its relationship to disease evolution and changes in the PSP Rating Scale.
| S-EPMC8119324 | biostudies-literature
Project description:Background and purposeProgressive supranuclear palsy (PSP) encompasses a broader range of disease courses than previously appreciated. The most frequent clinical presentations of PSP are Richardson syndrome (RS) and PSP with a predominant Parkinsonism phenotype (PSP-P). Time to reach gait dependence and cognitive impairment have been proposed as prognostic disease milestones. Genetic polymorphisms in TRIM11 and SLC2A13 genes have been associated with longer disease duration (DD).MethodsMethods used include retrospective chart review, genetic single nucleotide polymorphism analyses (in three cases), and neuropathology.ResultsWe identified four cases with long (>10-15 years) or very long (>15 years) DD. Stage 1 PSP tau pathology was present in two cases (one PSP-P and one undifferentiated phenotype), whereas pallidonigroluysian atrophy (PSP-RS) and Stage 4/6 (PSP-P) PSP pathology were found in the other two cases. Three cases were homozygous for the rs564309-C allele of the TRIM11 gene and the H1 MAPT haplotype. Two were heterozygous for rs2242367 (G/A) in SLC2A13, whereas the third was homozygous for the G-allele.ConclusionsWe propose a protracted course subtype of PSP (PC-PSP) based on clinical or neuropathological criteria in two cases with anatomically restricted PSP pathology, and very long DD and slower clinical progression in the other two cases. The presence of the rs564309-C allele may influence the protracted disease course. Crystallizing the concept of PC-PSP is important to further understand the pathobiology of tauopathies in line with current hypotheses of protein misfolding, seeding activity, and propagation.
| S-EPMC10276574 | biostudies-literature
Project description:IntroductionTremor is thought to be a rare feature of progressive supranuclear palsy (PSP).MethodsWe retrospectively reviewed the database of the CurePSP brain bank at Mayo Clinic Florida to retrieve all available clinical information for PSP patients. All patients underwent a standard neuropathological assessment and an immunohistochemical evaluation for tau and α-synuclein. DNA was genotyped for the MAPT H1/H2 haplotype.ResultsOf the 375 PSP patients identified, 344 had a documented presence or absence of tremor, which included 146 (42%) with tremor, including 29 (20%) with postural/action tremors, 16 (11%) with resting tremor, 7 (5%) with intention tremor, 20 (14%) with a combination of different types of tremor, and 74 (51%) patients who had tremor at some point during their illness, but details were unavailable. The tremor severity of 96% of the patients (54/55) who had this data was minimal to mild. The probability of observing a tremor during a neurological examination during the patient's illness was estimated to be ∼22%. PSP patients with postural/action tremors and PSP patients with resting tremor responded to carbidopa-levodopa therapy more frequently than PSP patients without tremor, although the therapy response was always transient. There were no significant differences in pathological findings between the tremor groups.ConclusionsTremor is an inconspicuous feature of PSP; however, 42% (146/344) of the PSP patients in our study presented some form of tremor. Because there is no curative therapy for PSP, carbidopa/levodopa therapy should be tried for patients with postural, action, and resting tremor.
| S-EPMC4887294 | biostudies-literature
Project description:Progressive supranuclear palsy (PSP) is a neurodegenerative syndrome that is clinically characterized by progressive postural instability, supranuclear gaze palsy, parkinsonism and cognitive decline. Pathologically, diagnosis of PSP is based on characteristic features, such as neurofibrillary tangles, neutrophil threads, tau-positive astrocytes and their processes in basal ganglia and brainstem, and the accumulation of 4 repeat tau protein. PSP is generally recognized as a sporadic disorder; however, understanding of genetic background of PSP has been expanding rapidly. Here we review relevant publications to outline the genetics of PSP. Although only small number of familial PSP cases have been reported, the recognition of familial PSP has been increasing. In some familial cases of clinically probable PSP, PSP pathologies were confirmed based on NINDS neuropathological diagnostic criteria. Several mutations in MAPT, the gene that causes a form of familial frontotemporal lobar degeneration with tauopathy, have been identified in both sporadic and familial PSP cases. The H1 haplotype of MAPT is a risk haplotype for PSP, and within H1, a sub-haplotype (H1c) is associated with PSP. A recent genome-wide association study on autopsyproven PSP revealed additional PSP risk alleles in STX6 and EIF2AK3. Several heredodegenerative parkinsonian disorders are referred to as PSP-look-alikes because their clinical phenotype, but not their pathology, mimics PSP. Due to the fast development of genomics and bioinformatics, more genetic factors related to PSP are expected to be discovered. Undoubtedly, these studies will provide a better understanding of the pathogenesis of PSP and clues for developing therapeutic strategies.
| S-EPMC4572662 | biostudies-literature