Macrophage Targeting Protects Nerve Structure and Improves Muscle Innervation in a Mouse Model of Charcot-Marie-Tooth...

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Macrophage targeting with c-FMS inhibitor PLX5622 previously alleviated demyelinating Charcot-Marie-Tooth (CMT) 1 forms.
• The role of macrophages in axonal CMT2 subtypes remained uninvestigated.

Purpose of the Study:

• To investigate the role of macrophages in axonal CMT2J neuropathy using a mouse model.
• To evaluate the therapeutic potential of targeting macrophages in CMT2J.

Main Methods:

• Utilized hemizygous P0T124M mice, a model for late-onset axonopathy and macrophage activation.
• Administered PLX5622, a CSF-1 receptor specific kinase (c-FMS) inhibitor, to target macrophages from 12 to 18 months of age.
• Assessed peripheral neuropathy, distal axonal degeneration, neuromuscular junction denervation, and motor function.

Main Results:

• PLX5622 treatment significantly ameliorated peripheral neuropathy in CMT2J mice.
• The treatment prevented distal axonal degeneration and denervation of neuromuscular junctions.
• Motor function was preserved in PLX5622-treated CMT2J mice.

Conclusions:

• Macrophage-mediated inflammation is a key driver of neuropathy in axonal CMT2J.
• Targeting macrophages represents a promising therapeutic strategy for both demyelinating and axonal forms of CMT.
• PLX5622 demonstrates significant therapeutic potential for CMT2J by mitigating macrophage-driven pathology.