Cryptic splicing of stathmin-2 and UNC13A mRNAs is a pathological hallmark of TDP-43-associated Alzheimer’s disease
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Published:2024-01-04
Issue:1
Volume:147
Page:
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ISSN:0001-6322
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Container-title:Acta Neuropathologica
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language:en
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Short-container-title:Acta Neuropathol
Author:
Agra Almeida Quadros Ana Rita, Li Zhaozhi, Wang Xue, Ndayambaje I. Sandra, Aryal Sandeep, Ramesh Nandini, Nolan Matthew, Jayakumar Rojashree, Han Yi, Stillman Hannah, Aguilar Corey, Wheeler Hayden J., Connors Theresa, Lopez-Erauskin Jone, Baughn Michael W., Melamed Ze’ev, Beccari Melinda S., Olmedo Martínez Laura, Canori Michael, Lee Chao-Zong, Moran Laura, Draper Isabelle, Kopin Alan S., Oakley Derek H., Dickson Dennis W., Cleveland Don W., Hyman Bradley T., Das Sudeshna, Ertekin-Taner NilüferORCID, Lagier-Tourenne ClotildeORCID
Abstract
AbstractNuclear clearance and cytoplasmic accumulations of the RNA-binding protein TDP-43 are pathological hallmarks in almost all patients with amyotrophic lateral sclerosis (ALS) and up to 50% of patients with frontotemporal dementia (FTD) and Alzheimer’s disease. In Alzheimer’s disease, TDP-43 pathology is predominantly observed in the limbic system and correlates with cognitive decline and reduced hippocampal volume. Disruption of nuclear TDP-43 function leads to abnormal RNA splicing and incorporation of erroneous cryptic exons in numerous transcripts including Stathmin-2 (STMN2, also known as SCG10) and UNC13A, recently reported in tissues from patients with ALS and FTD. Here, we identify both STMN2 and UNC13A cryptic exons in Alzheimer’s disease patients, that correlate with TDP-43 pathology burden, but not with amyloid-β or tau deposits. We also demonstrate that processing of the STMN2 pre-mRNA is more sensitive to TDP-43 loss of function than UNC13A. In addition, full-length RNAs encoding STMN2 and UNC13A are suppressed in large RNA-seq datasets generated from Alzheimer’s disease post-mortem brain tissue. Collectively, these results open exciting new avenues to use STMN2 and UNC13A as potential therapeutic targets in a broad range of neurodegenerative conditions with TDP-43 proteinopathy including Alzheimer’s disease.
Funder
BrightFocus Foundation Friedrich Naumann Stiftung Association for Frontotemporal Degeneration ALS Association Muscular Dystrophy Association National Institute on Aging CurePSP Mayo Clinic National Institute of Neurological Disorders and Stroke Robert Packard Center for ALS Research, Johns Hopkins University Alzheimer's Association
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology (clinical),Pathology and Forensic Medicine
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