Novel G342L MAPT mutation in familial Progressive Supranuclear Palsy Syndrome
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PROVIDER: PRJEB73767 | ENA |
REPOSITORIES: ENA
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Project description:The cerebrospinal fluid miRNAs expression was markedly altered in the patients with progressive supranuclear palsy and controls.
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Project description:A cerebrospinal fluid microRNA analysis of progressive supranuclear palsy.
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Project description:Progressive Supranuclear Palsy (PSP) is a clinically heterogeneous 4-repeat (4R)-tauopathy marked by variable progression and phenotypic diversity. We examined the distribution of high-molecular-weight tau (HMW-tau) species and 4R-tau seeding capacity across 25 PSP cases and 20 brain regions. HMW-tau levels varied regionally, with the temporal and motor cortices exhibiting the highest abundance. Using size-exclusion chromatography (SEC) and 4R-tau seed amplification assays (SAAs), we identified that HMW-tau fractions exhibit the greatest seeding activity. Proteomic and spatial transcriptomic analyses of the primary motor cortex revealed dysregulated adaptive immunity and metabolic pathways in high-seeder cases. Neuropathological clustering confirmed distinct profiles associated with tau seeding activity. These findings suggest that evaluating tau seeding capacity may offer valuable insights into the heterogeneity of PSP and its underlying molecular drivers.
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Project description:4R-Tau Seeding Activity Reveals Molecular Subtypes in Progressive Supranuclear Palsy
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Project description:Impact of Coding and Non-coding Variation in Progressive Supranuclear Palsy
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Project description:Human cerebrospinal fluid was collected from patients diagnosed with neurodegenerative diseases including multiple system atrophy (n=28), Parkinson’s disease (n=40), dementia with Lewy bodies (n=20), progressive supranuclear palsy (n=39) and from controls (n=17) in order to perform a comparative quantitative proteome profiling of cerebrospinal fluids from the five groups.
2022-08-12 | PXD026802 | Pride
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:Progressive supranuclear palsy (PSP) is a neurodegenerative movement and cognitive disorder characterized by abnormal accumulation of the microtubule-associated protein tau in the brain. Biochemically, inclusions in PSP are enriched for tau proteoforms with four microtubule-binding domain repeats (4R), an isoform that arises from alternative tau pre-mRNA splicing. While preferential aggregation and reduced degradation of 4R tau protein is thought to play a role in inclusion formation and toxicity, an alternative hypothesis is that altered expression of tau mRNA isoforms plays a causal role. This stems from the observation that PSP is associated with common variation in the tau gene (MAPT) at the 17q21.31 locus which contains low copy number repeats flanking a large recurrent genomic inversion. The complex genomic structural changes at the locus give rise to two dominant haplotypes, termed H1 and H2, that have the potential to markedly influence gene expression. Here, we explored haplotype-dependent differences in gene expression using a bulk RNA-seq dataset derived from human post-mortem brain tissue from PSP (n = 84) and controls (n = 77) using a rigorous computational pipeline, including alternative pre-mRNA splicing. We found 3579 differentially expressed genes in the temporal cortex and 10,011 in the cerebellum. We also found 7214 differential splicing events in the temporal cortex and 18,802 in the cerebellum. In the cerebellum, total tau mRNA levels and the proportion of transcripts encoding 4R tau were significantly increased in PSP compared to controls. In the temporal cortex, the proportion of reads that expressed 4R tau was increased in cases compared to controls. 4R tau mRNA levels were significantly associated with the H1 haplotype in the temporal cortex. Further, we observed a marked haplotype-dependent difference in KANSL1 expression that was strongly associated with H1 in both brain regions. These findings support the hypothesis that sporadic PSP is associated with haplotype-dependent increases in 4R tau mRNA that might play a causal role in this disorder.
| S-EPMC11330133 | biostudies-literature