Shared Genomic Architecture Between Schizophrenia and Multiple Sclerosis Identifies an Un-Drugged HCAR1 Neuroimmune...

Area of Science:

• Neuroimmunology
• Neurogenetics
• Molecular Biology

Background:

• Multiple Sclerosis (MS) pathogenesis involves macrophage infiltration into the brain.
• Current MS therapies like Dimethyl Fumarate target HCAR2, but HCAR1 remains uninvestigated.
• Genetic links between MS and Schizophrenia (SCZ) suggest shared regulatory mechanisms.

Purpose of the Study:

• To investigate the role of the HCAR tandem array in MS and SCZ pathogenesis.
• To identify the functional consequences of genetic variations within the HCAR regulatory domain.
• To explore HCAR1 as a potential therapeutic target for demyelinating diseases.

Main Methods:

• Cross-referencing genomic architectures of MS and SCZ.
• High-resolution expression quantitative trait loci (eQTL) mapping in human immune cells.
• Analysis of HCAR1 transcriptomic regulation in peripheral macrophages.

Main Results:

• A shared structural variation in the HCAR tandem regulatory domain is associated with MS and SCZ susceptibility.
• This variation leads to a specific transcriptomic collapse of HCAR1 in peripheral macrophages.
• Macrophages with reduced HCAR1 expression are unable to sense lactate, impairing negative feedback and promoting immune proliferation.

Conclusions:

• The HCAR tandem array functions as a critical neuroimmune switch.
• HCAR1 acts as a lactate sensor that regulates macrophage proliferation.
• Targeting the HCAR1 lactate brake presents a novel therapeutic strategy for MS and other demyelinating diseases.