A role for the spinal cord cholinergic neuron circadian clock in RNA metabolism and mediating ALS disease phenotypes

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Circadian clocks regulate physiological processes via transcription-translation feedback loops.
• RNA-binding proteins (RBPs) and alternative splicing are crucial for neuronal function and implicated in amyotrophic lateral sclerosis (ALS).
• Previous research suggests a link between circadian rhythms, RBPs, and alternative splicing, necessitating investigation in neurodegenerative diseases like ALS.

Purpose of the Study:

• To investigate the mechanistic connections between the circadian clock, RBPs, and alternative splicing in the context of ALS.
• To identify circadian regulation of ALS-associated genes and RBPs in spinal cord cholinergic neurons.
• To determine the role of the cholinergic neuron circadian clock in ALS pathogenesis.

Main Methods:

• Analysis of the rhythmic transcriptome in spinal cord cholinergic neurons.
• Demonstration of circadian regulation of ALS-linked RBPs and alternative splicing.
• Investigation of the effects of cell-type-specific Bmal1 deletion on motor neuron loss, axon degeneration, and alternative splicing.

Main Results:

• Enrichment of ALS and neurodegenerative disease genes in the spinal cord cholinergic neuron rhythmic transcriptome.
• Circadian regulation of ALS-linked RBPs and alternative splicing of genes involved in intracellular transport, cytoskeleton organization, and synaptic function.
• Cell-type-specific Bmal1 deletion led to motor neuron loss, axon degeneration, and altered splicing of ALS-linked genes and those involved in microtubule transport and postsynaptic organization.

Conclusions:

• The circadian clock in cholinergic neurons plays a significant role in regulating RBP function and alternative splicing.
• Circadian clock disruption in cholinergic neurons contributes to ALS disease phenotypes, including motor neuron degeneration and altered gene expression.
• These findings establish a novel link between circadian rhythms and ALS pathogenesis, highlighting potential therapeutic targets.