Cryptic splicing in synaptic and membrane excitability genes links TDP-43 loss to neuronal dysfunction

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• TDP-43 protein aggregation is central to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
• TDP-43 dysfunction leads to nuclear depletion and aberrant RNA splicing, including cryptic exon inclusion.
• While STMN2 and UNC13A are known targets, the full impact on neuronal function is not well understood.

Purpose of the Study:

• To identify novel TDP-43 splicing targets involved in neuronal excitability and synaptic function.
• To investigate the functional consequences of TDP-43-dependent cryptic splicing in human neurons.
• To explore therapeutic potential of targeting cryptic splicing in neurodegenerative disease models.

Main Methods:

• Utilized human stem cell-derived neurons to model TDP-43 pathology.
• Analyzed RNA splicing patterns and gene expression following TDP-43 reduction.
• Examined postmortem brain tissue from FTD patients.
• Employed antisense oligonucleotides to modulate specific cryptic splicing events.

Main Results:

• Identified KALRN, RAP1GAP, SYT7, and KCNQ2 as new TDP-43 splicing targets critical for neuronal function.
• Demonstrated that TDP-43 reduction induces cryptic splicing and downregulation of these genes, impairing neuronal excitability and synaptic transmission.
• Observed selective neuronal cryptic splicing in FTD patient brains.
• Showed partial to near-complete rescue of neuronal function by targeting cryptic splicing events.

Conclusions:

• TDP-43-dependent cryptic splicing in synaptic and excitability genes is a direct driver of neuronal dysfunction in ALS and FTD.
• This study establishes a mechanistic link between TDP-43 pathology and neurodegeneration.
• Targeting cryptic splicing represents a promising therapeutic avenue for neurodegenerative diseases associated with TDP-43.