CREB3 gain of function variants protect against ALS.

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss.
• Understanding the molecular mechanisms underlying ALS pathogenesis is crucial for developing effective therapies.

Purpose of the Study:

• To identify molecular markers associated with resilience in corticospinal neurons (CSN) in ALS.
• To investigate the role of the transcription factor CREB3 and its variants in ALS.
• To explore the therapeutic potential of CREB3 in ALS.

Main Methods:

• Comparative cross-species transcriptomics of CSN using snRNA-seq data from human postmortem tissues.
• Longitudinal RNA-seq on purified CSN from Sod1G86R mouse models.
• Genetic and epidemiologic analyses of ALS patients.
• Gain-of-function studies of the CREB3R119G variant.

Main Results:

• CSN in ALS exhibit endoplasmic reticulum (ER) stress and altered mRNA translation.
• The transcription factor CREB3 and its network are identified as resilience markers across various cell types in ALS.
• A rare variant, CREB3R119G (rs11538707), acts as a positive disease modifier in ALS.
• Gain of function for CREB3R119G reduces ALS risk and slows motor progression in patients.

Conclusions:

• CREB3 is a key molecular player in neuronal resilience against ALS.
• The CREB3R119G variant demonstrates potential as a protective factor against ALS development and progression.
• Targeting the CREB3 pathway may offer a novel therapeutic strategy for ALS.