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 pathology is a hallmark of neurodegenerative diseases like ALS and FTD.
• TDP-43 nuclear depletion causes aberrant RNA splicing, including cryptic exon inclusion.
• Known TDP-43 splicing targets like STMN2 and UNC13A are implicated, but broader impacts are unclear.

Purpose of the Study:

• To identify novel TDP-43 splicing targets critical for neuronal function.
• To investigate the functional consequences of TDP-43-dependent cryptic splicing in neurons.
• To explore therapeutic strategies targeting cryptic splicing in neurodegenerative diseases.

Main Methods:

• Utilized human stem cell-derived neurons to model TDP-43 reduction.
• Analyzed gene expression and RNA splicing patterns.
• Examined neuronal excitability and synaptic transmission.
• Investigated postmortem brain tissue from FTD patients.
• Employed antisense oligonucleotides to suppress cryptic splicing events.

Main Results:

• Identified KALRN, RAP1GAP, SYT7, and KCNQ2 as novel TDP-43 splicing targets.
• TDP-43 reduction led to cryptic splicing and downregulation of these genes, impairing neuronal excitability and synaptic transmission.
• Cryptic splicing events were observed in neurons with TDP-43 pathology in FTD brains.
• Antisense oligonucleotide treatment partially or fully restored neuronal function by suppressing cryptic splicing.

Conclusions:

• TDP-43-dependent cryptic splicing in synaptic and excitability genes directly drives neuronal dysfunction in ALS and FTD.
• This study establishes a mechanistic link between TDP-43 pathology and neurodegeneration.
• Targeting cryptic splicing represents a potential therapeutic approach for TDP-43 proteinopathies.