Differential modulation of the juxtaparanodal complex in Multiple Sclerosis

Area of Science:

• Neuroscience
• Neuroimmunology
• Cellular Biology

Background:

• Myelinated axons are organized into distinct domains, including paranodes and juxtaparanodes, crucial for neuronal function.
• Multiple Sclerosis (MS) is associated with demyelination and axonal damage, potentially affecting these specialized domains.
• Juxtaparanodal proteins, such as TAG-1, Caspr2, and voltage-gated potassium channels (VGKCs), play vital roles in axonal integrity and signaling.

Purpose of the Study:

• To investigate alterations in juxtaparanodal proteins (TAG-1, Caspr2, VGKCs) in normal-appearing white matter (NAWM), perilesion, and chronic lesion areas of MS patients.
• To determine the impact of MS on the molecular organization and maintenance of juxtaparanodes at both protein and mRNA levels.

Main Methods:

• Analysis of post-mortem white matter tissue from MS patients and controls.
• Assessment of protein and mRNA expression of TAG-1, Caspr2, and VGKCs.
• Immunohistochemistry to evaluate protein localization and clustering at juxtaparanodes.

Main Results:

• Reduced TAG-1 clustering in NAWM; TAG-1 and Caspr2 diffusion in perilesions and absence in lesions.
• Loss of VGKC enrichment at juxtaparanodes in NAWM, perilesions, and lesions.
• Significant upregulation of Caspr2 mRNA and transcriptional increase of paranodal Caspr in MS lesions, suggesting an axonal homeostatic response.

Conclusions:

• The molecular organization of juxtaparanodes is significantly compromised in MS lesions, perilesions, and even NAWM.
• Differential alterations in TAG-1, Caspr2, and VGKCs indicate widespread disruption of axonal domains in chronic MS.
• Axonal homeostatic mechanisms, including transcriptional upregulation of Caspr2, are activated in response to damage in MS lesions.