Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy DOI Creative Commons
Kristen Whitney, Won‐Min Song,

Abhijeet Sharma

et al.

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 148(1)

Published: Dec. 9, 2024

Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative tauopathy variably affecting brainstem and cortical structures, characterized by tau inclusions in neurons glia. The precise mechanism whereby these protein aggregates lead to cell death remains unclear. To investigate the contribution of different cellular abnormalities PSP pathogenesis, we performed single-nucleus RNA sequencing (snRNA-seq) analyzed 50,708 high quality nuclei targeting diencephalon, including subthalamic nucleus adjacent from human post-mortem brains with varying degrees pathology compared controls. Cell-type-specific differential expression pathway analysis identified both common discrete changes numerous pathways previously implicated other disorders. This included EIF2 signaling, an adaptive activated response diverse stressors, which was multiple vulnerable types validated independent snRNA-seq bulk RNA-seq datasets. Using immunohistochemistry, found that eIF2α positively correlated burden brain regions. Multiplex immunofluorescence localized positivity hyperphosphorylated (p-tau) positive ALDH1L1-positive astrocytes, supporting increased transcriptomic activation observed types. In conclusion, data provide insights into cell-type-specific pathological support hypothesis failure stress play mechanistic role pathogenesis progression PSP.

Language: Английский

Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes DOI Creative Commons
Kurt Farrell, Jack Humphrey, Timothy S. Chang

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Sept. 9, 2024

Language: Английский

Citations

9
DNA methylation as a contributor to dysregulation of STX6 and other frontotemporal lobar degeneration genetic risk-associated loci DOI Creative Commons
Naiomi Rambarack, Katherine Fodder, Megha Murthy

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 21, 2025

Frontotemporal Lobar Degeneration (FTLD) represents a spectrum of clinically, genetically, and pathologically heterogeneous neurodegenerative disorders characterised by progressive atrophy the frontal temporal lobes brain. The two major FTLD pathological subgroups are FTLD-TDP FTLD-tau. While majority cases sporadic, heterogeneity also exists within familial cases, typically involving mutations in MAPT, GRN or C9orf72, which is not fully explained known genetic mechanisms. We sought to address this gap investigating effect epigenetic modifications, specifically DNA methylation variation, on genes associated with risk different subtypes. compiled list using text-mining databases literature searches. Frontal cortex profiles were derived from three datasets containing FTLD-tau: FTLD1m (N = 23) type A C9orf72 mutation carriers TDP Type C sporadic FTLD2m 48) FTLD-Tau MAPT carriers, B FTLD3m 163) supranuclear palsy (PSP) corresponding controls. To investigate downstream effects further, we then leveraged transcriptomic proteomic for controls examine gene protein expression levels. Our analysis revealed shared promoter region hypomethylation STX6 across FTLD-tau subtypes, though largest size was observed PSP compared (delta-beta -32%, adjusted-p value=0.002). dysregulation Additionally, performed detailed examination subtypes without presence nominally significant differentially methylated CpGs variable positions genes, often unique patterns consequences gene/protein carriers. highlight contribution at regions regulating previously FTLD, including STX6. analysed relationship mechanism increase our understanding how these mechanisms interact FTLD.

Language: Английский

Citations

0
The Genetic Background of the Immunological and Inflammatory Aspects of Progressive Supranuclear Palsy DOI Open Access
Piotr Alster, Natalia Madetko‐Alster

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(9), P. 3927 - 3927

Published: April 22, 2025

Progressive supranuclear palsy (PSP) is a neurodegenerative disease, classified as an atypical Parkinsonian syndrome, that has been pathologically and clinically defined. The histopathological aspects of the disease include tufted astrocytes, while clinical features involve oculomotor dysfunction, postural instability, akinesia, cognitive impairment, language difficulties. Although PSP generally considered sporadic interest growing in its genetics, with contemporary research focusing on familial backgrounds neuroinflammation. Indeed, microglial activation other inflammatory mechanisms pathogenesis have extensively analyzed using genetic examinations to identify factors impacting neurodegeneration. As such, this review aims elaborate recent findings field.

Language: Английский

Citations

0
Single-cell transcriptomic and neuropathologic analysis reveals dysregulation of the integrated stress response in progressive supranuclear palsy DOI Creative Commons
Kristen Whitney, Won‐Min Song,

Abhijeet Sharma

et al.

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 148(1)

Published: Dec. 9, 2024

Progressive supranuclear palsy (PSP) is a sporadic neurodegenerative tauopathy variably affecting brainstem and cortical structures, characterized by tau inclusions in neurons glia. The precise mechanism whereby these protein aggregates lead to cell death remains unclear. To investigate the contribution of different cellular abnormalities PSP pathogenesis, we performed single-nucleus RNA sequencing (snRNA-seq) analyzed 50,708 high quality nuclei targeting diencephalon, including subthalamic nucleus adjacent from human post-mortem brains with varying degrees pathology compared controls. Cell-type-specific differential expression pathway analysis identified both common discrete changes numerous pathways previously implicated other disorders. This included EIF2 signaling, an adaptive activated response diverse stressors, which was multiple vulnerable types validated independent snRNA-seq bulk RNA-seq datasets. Using immunohistochemistry, found that eIF2α positively correlated burden brain regions. Multiplex immunofluorescence localized positivity hyperphosphorylated (p-tau) positive ALDH1L1-positive astrocytes, supporting increased transcriptomic activation observed types. In conclusion, data provide insights into cell-type-specific pathological support hypothesis failure stress play mechanistic role pathogenesis progression PSP.

Language: Английский

Citations

2