LRRC4 functions as a neuron-protective role in experimental autoimmune encephalomyelitis.

Area of Science:

• Neuroscience
• Immunology

Background:

• Leucine rich repeat containing 4 (LRRC4), also known as netrin-G ligand-2 (NGL-2), is crucial for synapse formation and axon development.
• Mutations in LRRC4 are linked to Autism Spectrum Disorder (ASD) and intellectual disability.
• Multiple sclerosis (MS) is a neuroinflammatory disease characterized by demyelination and neurodegeneration in the spinal cord.

Purpose of the Study:

• To investigate the role of LRRC4 in spinal cord neuron-associated diseases, specifically in the context of experimental autoimmune encephalomyelitis (EAE).
• To explore LRRC4's potential as a therapeutic target for MS.

Main Methods:

• LRRC4 expression was analyzed in the central nervous system (CNS) of EAE mice.
• LRRC4 knockout (LRRC4-/-) mice were used to study disease progression and pathology.
• Flow cytometry, RNA sequencing, and immunohistochemistry were employed to assess immune responses and gene expression.
• Adeno-associated virus (AAV) vectors were used to evaluate the therapeutic potential of LRRC4 overexpression.

Main Results:

• LRRC4 expression was decreased in the spinal cords of EAE mice.
• LRRC4 deficiency accelerated EAE progression, leading to severe myelin degeneration and leukocyte infiltration.
• LRRC4 deficiency elevated Rab7b and NF-κB p65, increasing pro-inflammatory cytokines (IL-6, IFN-γ) and exacerbating Th1 immune responses.
• Overexpression of LRRC4 alleviated EAE symptoms and protected neurons.

Conclusions:

• LRRC4 exhibits a neuroprotective role in EAE progression.
• LRRC4 may serve as a potential therapeutic target for supporting MS treatment.