Project description:Progressive Supranuclear palsy (PSP) is a 4-repeat (4-R) tauopathy. We hypothesized that the molecular diversity of tau could explain the heterogeneity seen in PSP disease progression. To test this hypothesis, we performed an extensive biochemical characterisation of the high molecular weight tau species (HMW-Tau) in 20 different brain regions of 25 PSP patients. To identify factors that contribute to these differences, we performed proteomic analysis that revealed key mechanistic pathways, in particular those involving the immune system, that defined patients demonstrating high and low tau seeding capacity.
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.
Project description:Background: The molecular mechanisms of tauopathies, characterized by intracellular accumulation of abnormal tau encoded by MAPT, remain poorly understood. Objectives: To identify proteins associated with the primary tauopathies corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), as well as the secondary tauopathy Alzheimer’s disease (AD), using mass spectrometry. Methods: Total homogenates were prepared from human postmortem brains of AD (n = 4), CBD (n = 4), PSP (n = 4), and their respective controls (n = 4), and analyzed by mass spectrometry. Protein levels were compared across the four groups, and proteins showing statistically significant differences were subsequently examined using functional enrichment and protein–protein interaction (PPI) analyses. For a subset of the proteins that showed significant differences, immunohistochemistry was performed to determine their distribution in the brain. Furthermore, single-nucleus RNA sequencing data were analyzed to evaluate the corresponding gene expression across the four groups in a cell-type–specific manner at the RNA level. Results: In the four-group comparison, 859, 114, 6, and 1 proteins showed P values < 0.05, < 0.01, < 0.005, and < 0.001, respectively. We subsequently focused on the six proteins with P values < 0.005 (AK3, ATP5PD, COX7C, PPA1, PREP, and UQCRC1) and performed functional enrichment and PPI analyses. These analyses revealed that the identified tauopathy-related proteins were shown to be mainly involved in mitochondrial function. Discussion: Age-related mitochondrial dysfunction could influence the onset and progression of tauopathies.
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.
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.
Project description:Tauopathies are a group of neurodegenerative diseases characterised by the abnormal accumulation of tau protein within neural and glial cells. The molecular mechanisms of tauopathies remain poorly understood. To identify proteins whose abundance is altered by the disease group, we performed a proteomic analysis of brain homogenate from patients with three tauopathy-related diseases: corticobasal degeneration, progressive supranuclear palsy and Alzheimer's disease.