Nogo receptor antagonizes p75NTR-dependent motor neuron death

PNAS, 2008 · DOI: 10.1073/pnas.0703842105 · Published: January 15, 2008

Simple Explanation

The Nogo-66 receptor (NgR) is known for its role in limiting axon regeneration in the central nervous system. This study reveals a new function: NgR can protect motor neurons from death. Two peptides, Pep4 and NEP1–40, derived from the Nogo-66 sequence, prevent the death of embryonic motor neurons caused by NGF stimulation of p75NTR, a receptor associated with cell death. These peptides also protect spinal cord motor neurons from dying after nerve damage (axotomy) in newborn mice, suggesting NgR has a role in keeping neurons alive during development and degeneration.

Study Duration

Not specified

Participants

Mouse embryos, cultured embryonic motor neurons, motor neuron-like cell line NSC34

Evidence Level

Not specified

Key Findings

1
NgR, LINGO-1, and p75NTR mRNAs are expressed in cultures of purified embryonic motor neurons and NSC34 cells, indicating that NgR activation could involve p75NTR in this paradigm.
2
Nogo-66 peptides, Pep4 and NEP1-40, prevent p75NTR-dependent motor neuron death in vitro when added at the same doses as those found to regulate neurite outgrowth.
3
Both Nogo-66 peptides abolished post-axotomy ipsilateral motor neuron loss compared with vehicle-treated animals, demonstrating neuroprotective potential in vivo after sciatic nerve axotomy.

Research Summary

This study investigates the role of Nogo-66 receptor (NgR) in motor neuron survival, revealing that peptides derived from the Nogo-66 sequence, Pep4 and NEP1-40, can prevent p75NTR-dependent motor neuron death in vitro and in vivo. Experiments show that NgR, LINGO-1, and p75NTR are co-expressed in motor neurons, and that Pep4 and NEP1-40 protect cultured embryonic motor neurons against NGF/p75NTR-induced cell death and motor neuron loss after sciatic nerve axotomy in neonate mice. The findings suggest a previously undescribed function for NgR in the CNS, indicating its potential as a therapeutic target for motor neuron diseases, using pharmacological agents targeting the receptor.

Practical Implications

Therapeutic Target for Motor Neuron Diseases

The discovery that NgR can promote motor neuron survival suggests that it could be a therapeutic target for motor neuron diseases such as ALS.

Understanding Axon Regeneration

The finding that NgR, known for limiting axon regeneration, can also promote neuronal survival adds complexity to our understanding of axon regeneration and neuronal protection.

Drug Development

The study highlights Pep4 and NEP1-40 as potential drug candidates for promoting motor neuron survival in conditions of nerve injury or neurodegenerative diseases.

Study Limitations

1
The exact mechanisms of NgR-mediated neuroprotection are not fully elucidated.
2
The study primarily focuses on embryonic and neonatal motor neurons, and the findings may not be directly applicable to adult motor neurons.
3
Compensatory mechanisms in NgR knockout mice may mask the full extent of NgR's role in motor neuron survival.

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