Work

TDP‐43 proteinopathy induced transcriptional alterations in Alzheimer’s disease

Year: 2024

Type: article

Abstract: BACKGROUND: TDP-43 is an RNA binding protein that is a pathological hallmark of multiple neurodegenerative diseases including Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). The frequency of observed TDP-43 pathology is estimated at 97% in ALS, 45% in FTD and 40-57% in AD and is characterized by a mislocalization of TDP-43 from the nucleus to the cytoplasm. Indeed, TDP-43 is the third most common proteinopathy in AD, behind only Amyloid beta and Tau. The normal function of TDP-43 has been linked to multiple steps in RNA processing including transcription, splicing, RNA transport, stability, localization, and translation. Most studies aimed at understanding TDP-43 pathology have been performed in the context of ALS and FTD, while little is known about the molecular mechanisms and consequences of TDP-43 pathology in AD. We hypothesize that TDP-43 dependent alterations in gene expression in neurons with TDP-43 pathology are contributing to neuronal dysfunction and degeneration in AD and related dementias. METHODS: To test this hypothesis, we sorted neuronal nuclei with normal and depleted TDP-43 levels from human post-mortem AD and Mild Cognitive Impairment (MCI) patients as well as Non-neurological Disease (ND) Controls. RESULTS: RNA sequencing results from these sorted nuclear isolates show substantial genome wide transcriptional alterations in gene expression as well as alternative splicing, and TDP-43-associated cryptic exon inclusion. CONCLUSIONS: These results support the significant role of TDP-43 pathology on the transcriptome of up to half of AD patients and the need for further exploration of a common but overlooked aspect of the most common progressive dementia in patients today.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz.089794

Author: Ryan S Pevey

Institutions: Barrow Neurological Institute, Arizona State University

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $4,000