Integrative multiomic analysis links TDP-43-driven splicing defects to cascading proteomic disruption of ALS/FTD...

Area of Science:

• Neuroscience
• Molecular Biology
• Genomics

Background:

• Loss of nuclear TDP-43 is a key feature in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• TDP-43 regulates RNA processing, including the repression of cryptic exons, but the full impact of its loss is not understood.

Purpose of the Study:

• To investigate the systems-level consequences of TDP-43 loss in human neurons.
• To identify molecular cascades and potential therapeutic targets for ALS and FTD.

Main Methods:

• Generated multiomic datasets (RNA-seq, proteomics) from human iPSC-derived neurons depleted of TDP-43.
• Performed integrative network analysis to identify disease-specific subnetworks.
• Experimentally validated network-predicted cryptic splicing effects.

Main Results:

• Genes with cryptic exon expression showed the most significant protein reductions.
• Nearly half of differentially expressed proteins were not directly linked to mis-splicing or differential gene expression.
• Identified a disease-specific subnetwork of over 700 proteins involved in mRNA processing, synaptic function, and autophagy.
• Discovered convergent protein and pathway disruptions in post-mortem ALS and FTD samples.

Conclusions:

• TDP-43 loss triggers complex molecular cascades beyond simple mis-splicing.
• Cryptic splicing and other mechanisms contribute to protein dysregulation in ALS/FTD.
• Identified specific genes (ATG4B, STMN2, DAPK1) and pathways as potential therapeutic targets for ALS and FTD.