Transcriptomic analysis of frontotemporal lobar degeneration with TDP-43 pathology reveals cellular alterations across multiple brain regions

Frontotemporal lobar degeneration (FTLD) is a group of heterogeneous neurodegenerative disorders affecting the frontal and temporal lobes of the brain. Nuclear loss and cytoplasmic aggregation of the RNA-binding protein TDP-43 represents the major FTLD pathology, known as FTLD-TDP. To date, there is...

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Bibliographic Details
Published in:Acta neuropathologica 2022-03, Vol.143 (3), p.383-401
Main Authors: Hasan, Rahat, Humphrey, Jack, Bettencourt, Conceição, Newcombe, Jia, Lashley, Tammaryn, Fratta, Pietro, Raj, Towfique
Format: Article
Language:English
Subjects:
Astrocytes
Atrophy
Autopsy
Brain
Brain - pathology
Cerebellum
Comparative analysis
Cortex (frontal)
Cortex (temporal)
Development and progression
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Endothelial cells
Endothelial Cells - pathology
Frontotemporal dementia
Frontotemporal Dementia - pathology
Frontotemporal Lobar Degeneration - pathology
Gene expression
Humans
Immune response
Medicine
Medicine & Public Health
Microglia
Molecular modelling
Nervous system diseases
Neurodegeneration
Neurodegenerative diseases
Neurons
Neurosciences
Oligodendrocytes
Original Paper
Pathology
Pericytes
Protein binding
RNA
RNA-binding protein
Transcription
Transcriptome
Transcriptomes
Transcriptomics
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Summary:Frontotemporal lobar degeneration (FTLD) is a group of heterogeneous neurodegenerative disorders affecting the frontal and temporal lobes of the brain. Nuclear loss and cytoplasmic aggregation of the RNA-binding protein TDP-43 represents the major FTLD pathology, known as FTLD-TDP. To date, there is no effective treatment for FTLD-TDP due to an incomplete understanding of the molecular mechanisms underlying disease development. Here we compared postmortem tissue RNA-seq transcriptomes from the frontal cortex, temporal cortex, and cerebellum between 28 controls and 30 FTLD-TDP patients to profile changes in cell-type composition, gene expression and transcript usage. We observed downregulation of neuronal markers in all three regions of the brain, accompanied by upregulation of microglia, astrocytes, and oligodendrocytes, as well as endothelial cells and pericytes, suggesting shifts in both immune activation and within the vasculature. We validate our estimates of neuronal loss using neuropathological atrophy scores and show that neuronal loss in the cortex can be mainly attributed to excitatory neurons, and that increases in microglial and endothelial cell expression are highly correlated with neuronal loss. All our analyses identified a strong involvement of the cerebellum in the neurodegenerative process of FTLD-TDP. Altogether, our data provides a detailed landscape of gene expression alterations to help unravel relevant disease mechanisms in FTLD.
ISSN:0001-6322
1432-0533
DOI:10.1007/s00401-021-02399-9