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SARM1 Inhibition in Three Mouse Models of Charcot-Marie-Tooth Disease
Alaura D Rice1, Abigail L D Tadenev1, Timothy J Hines1
1The Jackson Laboratory, Bar Harbor, Maine, USA.
Background:
Charcot-Marie-Tooth (CMT) disease can be caused by mutations in over 100 different genes, most of which lead to demyelination (type 1) or degeneration (type 2) of peripheral motor and sensory axons. SARM1 is a protein involved in the active process of Wallerian degeneration after axonal injury. Inhibition of SARM1 protects against axon degeneration following injury or in cases such as chemotherapy-induced peripheral neuropathy. However, the effects of SARM1 inhibition on axon degeneration in genetic diseases such as CMT are less clear.
Aims:
Here we tested whether SARM1 inhibition may be of benefit in three different mouse models of axonal CMT: GarsETAQ/CTM2D, NeflN98S/CMT2E, and Ighmbp2Y918C/CMT2S.
Methods:
For these proof-of-concept studies, mice were treated as neonates with an AAV9 to deliver a dominant negative SARM1 construct (dnSARM1) to the nervous system by intracerebroventricular injection. At ages appropriate for each mouse model, animals were then evaluated with a combination of behavioral, neurophysiological, and histological outcomes.
Results:
We reproduced the protective effects of the dnSARM1 construct in positive control experiments following sciatic nerve crush. However, we did not see a change in the phenotypes of any of the CMT mouse models examined. The neuropathy-related phenotypes neither worsened nor improved. Wild-type littermate controls treated with the AAV9 dnSARM1 had minor reductions in body weight and variable changes in motor performance compared to untreated controls, but no deficits by neurophysiology or histology.
Interpretation:
Inhibiting SARM1 using a virally delivered dominant negative construct was not efficacious in any of the three mouse models of CMT we tested. These mouse models were chosen for their relevance to the human disease and their prominent axon degeneration, and not for metabolic changes that would suggest SARM1 as a therapeutic target. SARM1 inhibition may remain an option for some forms of CMT, but a method for prescreening CMT subtypes to predict efficacy is needed.
Insights
SARM1 inhibition did not improve axon degeneration in three mouse models of Charcot-Marie-Tooth (CMT) disease. Further research is needed to identify which CMT subtypes might benefit from SARM1 inhibition therapies.
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 GarsETAQ/CTM2D, NeflN98S/CMT2E, and Ighmbp2Y918C/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.
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