AI Article Synopsis
- Aging is a significant risk factor in neurodegenerative diseases, and studying neuronal aging in controlled backgrounds can help understand the relationship between aging and neurodegeneration.
- In Huntington's disease, researchers found that the protein RCAN1 increases with age and its reduction can protect against neuron degeneration in affected individuals.
- Targeting RCAN1, either through genetic modification or the drug G2-115, enhances neuronal resilience by improving gene accessibility linked to longevity and autophagy.
Article Abstract
Aging is a common risk factor in neurodegenerative disorders. Investigating neuronal aging in an isogenic background stands to facilitate analysis of the interplay between neuronal aging and neurodegeneration. Here we perform direct neuronal reprogramming of longitudinally collected human fibroblasts to reveal genetic pathways altered at different ages. Comparative transcriptome analysis of longitudinally aged striatal medium spiny neurons (MSNs) in Huntington's disease identified pathways involving RCAN1, a negative regulator of calcineurin. Notably, RCAN1 protein increased with age in reprogrammed MSNs as well as in human postmortem striatum and RCAN1 knockdown rescued patient-derived MSNs of Huntington's disease from degeneration. RCAN1 knockdown enhanced chromatin accessibility of genes involved in longevity and autophagy, mediated through enhanced calcineurin activity, leading to TFEB's nuclear localization by dephosphorylation. Furthermore, G2-115, an analog of glibenclamide with autophagy-enhancing activities, reduced the RCAN1-calcineurin interaction, phenocopying the effect of RCAN1 knockdown. Our results demonstrate that targeting RCAN1 genetically or pharmacologically can increase neuronal resilience in Huntington's disease.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456361 | PMC |
| http://dx.doi.org/10.1038/s43587-023-00538-3 | DOI Listing |
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