Research Spotlight: Exploring a New Approach to Manage and Diagnose a Devastating Subset of Alzheimer’s Disease

Ana Rita Agra de Almeida Quadros, PhD, a research fellow in the Department of Neurology at Massachusetts General Hospital, is co-lead author of a new study in Acta Neuropathologica, Cryptic Splicing of Stathmin-2 and unc13a Mrnas Is a Pathological Hallmark of Tdp-43-Associated Alzheimer’s Disease.

Clotilde Lagier-Tourenne, PhD, and Sudeshna Das, PhD, of the Department of Neurology at Mass General are co-corresponding authors along with Nilüfer Ertekin-Taner, MD, PhD, of the Mayo Clinic.

Summary:

Alzheimer's disease is characterized by harmful protein buildup in the brain, causing neurodegeneration. A key protein, TDP-43, abnormally accumulates in about half of Alzheimer's cases, which affects TDP43 normal function.

Recently, we and others, found that two vital proteins for brain cell function, Stathmin-2 and UNC13A, are reduced in cells with abnormal TDP-43 localization.

In this study, we show that Stathmin-2 and UNC13A, undergo changes specifically in Alzheimer’s patients with abnormal TDP-43.

This insight opens possibilities for future treatments targeting these protein alterations, offering a new approach to manage and diagnose Alzheimer’s disease.

What Question Were You Investigating with this Study?

Are STMN2 and UNC13A equally sensitive to mis-splicing from TDP-43 loss?

Can detection of STMN2 and UNC13A cryptic exons in Alzheimer’s disease distinguish between patients with and without TDP-43 pathology?

What Was Unique About Your Approach

We used human neuroblastoma cell lines, postmortem brain tissue, and publicly available RNAseq datasets.

What Were Your Findings?

STMN2 and UNC13A cryptic exons are detected in post-mortem tissue of a subset of patients with Alzheimer’s disease, and this detection correlates with the presence of TDP-43 pathology.

The detection of STMN2 and UNC13A cryptic exons correlates with the burden of TDP-43 pathology but not with amyloid beta or tau.

Analysis of two independent large RNA-seq datasets identifies disruption of STMN2 and UNC13A in Alzheimer’s disease patients.

STMN2 transcripts are more sensitive to TDP-43 loss-of-function than the transcripts encoding UNC13A.

What are the Clinical Implications or Potential Patient Impact?

Even though there are not yet reliable biomarkers based on the detection of STMN2 or UNC13A cryptic exons, development of these approaches may have ground-breaking implications for subcategorization of patients.

In addition, we recently demonstrated the ability of steric binding ASOs to prevent mis-splicing and restore stathmin-2 protein level in TDP-43 deficient neurons and mouse brain, providing support for restoration of STMN2 as a potential therapeutic approach in TDP-43 proteinopathies, including Alzheimer’s disease.

What are the Next Steps?

Developing methods that can detect accurately and with high sensitivity STMN2 and UNC13A cryptic exons in live patients, which potentially could be used as biomarkers.

Performing RNAseq in amygdala of patients with and without TDP-43 pathology to explore further TDP-43 RNA targets in Alzheimer's disease.

Paper Cited:

Agra Almeida Quadros, A. R., Li, Z., Wang, X., Ndayambaje, I. S., Aryal, S., Ramesh, N., Nolan, M., Jayakumar, R., Han, Y., Stillman, H., Aguilar, C., Wheeler, H. J., Connors, T., Lopez-Erauskin, J., Baughn, M. W., Melamed, Z., Beccari, M. S., Olmedo Martínez, L., Canori, M., Lee, C. Z., … Lagier-Tourenne, C. (2024). Cryptic splicing of stathmin-2 and UNC13A mRNAs is a pathological hallmark of TDP-43-associated Alzheimer's disease. Acta neuropathologica, 147(1), 9. https://doi.org/10.1007/s00401-023-02655-0

About the Massachusetts General Hospital

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. MGH is a founding member of the Mass General Brigham healthcare system.