Cryptic splicing of stathmin-2 and UNC13A mRNAs is a pathological hallmark of TDP-43-associated Alzheimer’s disease

Ana Rita Agra Almeida Quadros, Zhaozhi Li, Xue Wang, I. Sandra Ndayambaje, Sandeep Aryal, Nandini Ramesh, Matthew Nolan, Rojashree Jayakumar, Yi Han, Hannah Stillman, Corey Aguilar, Hayden J. Wheeler, Theresa Connors, Jone Lopez-Erauskin, Michael W. Baughn, Ze’ev Melamed, Melinda S. Beccari, Laura Olmedo Martínez, Michael Canori, Chao Zong LeeLaura Moran, Isabelle Draper, Alan S. Kopin, Derek H. Oakley, Dennis W. Dickson, Don W. Cleveland, Bradley T. Hyman, Sudeshna Das*, Nilüfer Ertekin-Taner*, Clotilde Lagier-Tourenne*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Nuclear 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.

Original languageAmerican English
Article number9
JournalActa Neuropathologica
Volume147
Issue number1
DOIs
StatePublished - 4 Jan 2024
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2024, The Author(s).

Keywords

  • Alzheimer’s disease
  • Cryptic exons
  • SCG-10
  • Stathmin-2
  • TARDBP
  • TDP-43
  • UNC13A

Fingerprint

Dive into the research topics of 'Cryptic splicing of stathmin-2 and UNC13A mRNAs is a pathological hallmark of TDP-43-associated Alzheimer’s disease'. Together they form a unique fingerprint.

Cite this