Embryonic motor neuron programming factors reactivate immature gene expression and suppress ALS pathologies in postnatal motor neurons

Lowry, E. R.; Patel, T.; Costa, J. A.; Chang, E.; Tariq, S.; Melikyan, H.; Davis, I. M.; Aziz, S.; Dermentzaki, G.; Lotti, F.; Wichterle, H.

doi:10.1101/2024.04.03.587963

bioRxiv · 10.1101/2024.04.03.587963

Embryonic motor neuron programming factors reactivate immature gene expression and suppress ALS pathologies in postnatal motor neurons

Lowry, E. R.·Patel, T.·Costa, J. A.·Chang, E.·Tariq, S.·Melikyan, H.·Davis, I. M.·Aziz, S.·Dermentzaki, G.·Lotti, F.·Wichterle, H.

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Abstract

Aging is a major risk factor in amyotrophic lateral sclerosis (ALS) and other adult-onset neurodegenerative disorders. Whereas young neurons are capable of buffering disease-causing stresses, mature neurons lose this ability and degenerate over time. We hypothesized that the resilience of young motor neurons could be restored by re-expression of the embryonic motor neuron selector transcription factors ISL1 and LHX3. We found that viral re-expression of ISL1 and LHX3 reactivates aspects of the youthful gene expression program in mature motor neurons and alleviates key disease-relevant phenotypes in the SOD1G93A mouse model of ALS. Our results suggest that redeployment of lineage-specific neuronal selector transcription factors can be an effective strategy to attenuate age-dependent phenotypes in neurodegenerative disease.

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Lowry, E. R., Patel, T., Costa, J. A., Chang, E., Tariq, S., Melikyan, H., Davis, I. M., Aziz, S., Dermentzaki, G., Lotti, F., Wichterle, H.. 2024-04-05. Embryonic motor neuron programming factors reactivate immature gene expression and suppress ALS pathologies in postnatal motor neurons. https://doi.org/10.1101/2024.04.03.587963

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