A human forebrain organoid model phenocopies dysregulated RNA and protein homeostasis in ALS/FTD-associated TDP-43 proteinopathies.

ABSTRACT:

Background

TAR DNA-binding protein 43 (TDP-43) proteinopathy is a central hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet current experimental models fail to reproduce the full pathological spectrum without external stress or TDP-43 overexpression. This study aims to establish a human induced pluripotent stem cells (iPSC)-derived system that spontaneously manifests TDP-43 pathology driven by an ALS-associated TDP-43 mutation.

Methods

We generated forebrain 3-D organoid cultures from iPSC carrying the TDP-43 K181E patient mutation. Single-cell RNA sequencing was used to define transcriptional alterations across cell types, and enhanced crosslinking immunoprecipitation (eCLIP) was applied to examine the global RNA binding and splicing def

SUBMITTER: Zhang Q 

PROVIDER: S-EPMC12642313 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature