SARM1 Inhibition in Three Mouse Models of Charcot-Marie-Tooth Disease.

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Charcot-Marie-Tooth (CMT) disease involves over 100 gene mutations, leading to peripheral axon demyelination or degeneration.
• SARM1 protein drives Wallerian degeneration after axonal injury and is a target for neuroprotection.
• The efficacy of SARM1 inhibition in genetic CMT forms of axon degeneration remains unclear.

Purpose of the Study:

• To investigate the therapeutic potential of SARM1 inhibition in three distinct genetic mouse models of axonal Charcot-Marie-Tooth (CMT) disease.
• To evaluate the effects of a dominant-negative SARM1 construct (dnSARM1) on neuropathy phenotypes in Gars^ETAQ/CTM2D, Nefl^N98S/CMT2E, and Ighmbp2^Y918C/CMT2S mice.

Main Methods:

• Neonatal mice received intracerebroventricular injections of an AAV9 vector carrying a dominant-negative SARM1 construct (dnSARM1).
• Mice were assessed using behavioral, neurophysiological, and histological analyses at ages relevant to each CMT model.
• Positive control experiments involved sciatic nerve crush to validate dnSARM1 neuroprotective effects.

Main Results:

• The dnSARM1 construct demonstrated protective effects in sciatic nerve crush controls, as expected.
• No significant improvement or worsening of neuropathy-related phenotypes was observed in any of the three CMT mouse models.
• Wild-type mice treated with dnSARM1 showed minor weight reduction and variable motor changes, but no neurophysiological or histological deficits.

Conclusions:

• Viral delivery of a dominant-negative SARM1 construct was ineffective in ameliorating axon degeneration in the tested CMT mouse models.
• The tested CMT models exhibit prominent axon degeneration but lack metabolic changes suggesting SARM1 as a direct therapeutic target.
• Developing methods to prescreen CMT subtypes is crucial for predicting the efficacy of SARM1 inhibition therapies.