That’s a Wrap! Molecular Drivers Governing Neuronal Nogo Receptor-Dependent Myelin Plasticity and Integrity

Frontiers in Cellular Neuroscience, 2020 · DOI: 10.3389/fncel.2020.00227 · Published: August 4, 2020

Simple Explanation

Myelin, essential for fast nerve signal transmission, is dynamically maintained and altered under neuronal control. Disruption of this control can lead to neurodegeneration. This review focuses on myelin-associated inhibitory factors (MAIFs) and Nogo receptor 1 (NgR1), key players in neural injury. NgR1, beyond its role in inhibiting neurite sprouting, controls axo-myelin interactions and Nogo-A binding at axo-dendritic and axo-glial synapses. This review analyzes how neuronal NgR1 regulates myelin thickness and plasticity in both normal and disease conditions. The review discusses NgR1's role in regulating paranodal and juxtaparanodal domains via signal transduction cascades crucial for action potential propagation. Therapeutics targeting NgR1 signaling are being developed, highlighting the clinical significance of understanding NgR1's regulatory role.

Study Duration

Not specified

Participants

ngr1+/+ and ngr1−/− mice, MS patients

Evidence Level

Not specified

Key Findings

1
NgR1 regulates the distribution of Caspr, a paranodal protein, influencing the intramembranous cleavage of the protein at the junction. This finding correlated with altered ultrastructural organization at the paranode and internode of ngr1−/−mice.
2
ngr1−/− mice exhibit immature paranodal junctions and internodal myelin sheaths with constant myelin turnover. These molecular and ultrastructural findings were also electrophysiologically verified by delayed latency in CAP recordings of ngr1−/−when compared with wild-type mice.
3
Increased NgR1 expression in MS tissue is associated with elevated Reelin-mediated cleavage of Caspr, significant ion channel re-distribution along the axons and potentiated axonal damage.

Research Summary

This review explores the molecular mechanisms by which neuronal Nogo receptor 1 (NgR1) regulates myelin plasticity and integrity, particularly focusing on axo-myelin interactions and paranodal domain regulation. Studies on ngr1−/− mice reveal altered paranodal structure, Caspr distribution, and myelin turnover, suggesting a critical role for NgR1 in maintaining proper myelin architecture and function. The review highlights the potential of targeting NgR1-dependent signaling for therapeutic interventions in neurodegenerative diseases, emphasizing the need for further research into the complex interplay between NgR1, myelin dynamics, and axonal integrity.

Practical Implications

Therapeutic Development

Targeting NgR1-dependent signaling may offer new therapeutic avenues for treating neurodegenerative diseases like multiple sclerosis.

Understanding Myelin Plasticity

Further research into NgR1's role in myelin plasticity could enhance understanding of learning, cognition, and neural repair mechanisms.

Clinical Significance

Comprehensive investigation of NgR1's regulatory role in the axo-myelinic interface is crucial for developing effective clinical strategies.

Study Limitations

1
The precise neurophysiological roles of NgR1 in gait regulation need further investigation.
2
The endogenous activity innate to ngr1−/−CNS tissues, as a consequence of potentiated clearance of unstructured myelin, warrants further investigation.
3
Future research should involve investigations into CNS remyelination in adult ngr1−/− mice where specific demyelinating lesions are observed during the repair.

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