Cryptic Splicing in ALS: From Driving Disease Progression to Unlocking Novel Therapeutics

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• TDP-43 protein mislocalization is a hallmark of amyotrophic lateral sclerosis (ALS).
• Both loss- and gain-of-function mechanisms of TDP-43 contribute to ALS pathogenesis.
• Cryptic splicing events are downstream consequences of TDP-43 nuclear clearance.

Purpose of the Study:

• To elucidate the downstream effects of nuclear TDP-43 loss on neuronal health.
• To highlight the role of cryptic splicing in perpetuating neuronal dysfunction in ALS.
• To explore therapeutic potential of targeting cryptic splicing in TDP-43 proteinopathies.

Main Methods:

• Analysis of TDP-43's role in RNA processing.
• Investigation of cellular proteostasis mechanisms.
• Study of gene expression changes related to axonal homeostasis and synaptic transmission.

Main Results:

• Loss of nuclear TDP-43 triggers events impairing cellular proteostasis.
• A positive feedback loop involving cryptic splicing perpetuates neuronal dysfunction.
• Cryptic splicing affects genes crucial for axonal homeostasis and synaptic transmission.

Conclusions:

• Nuclear TDP-43 loss drives a cascade leading to impaired proteostasis and neuronal dysfunction.
• Cryptic splicing represents a key mechanism in ALS pathogenesis.
• Targeting cryptic splicing offers novel therapeutic strategies for TDP-43 proteinopathies.