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Mechanism for the modifier effect of RCAN1 in neurodegeneration of Huntington’s disease in patient-derived neurons [ATAC-Seq]

ABSTRACT: Genome-wide association studies have identified Genetic Modifiers of HD (GeM-HD) comprised of polymorphic gene variants associated with accelerated or delayed onset of Huntington’s disease (HD). However, GeM-HD genes that contribute to neurodegeneration in HD remain underexplored. Here, we used medium spiny neurons (MSNs) directly reprogrammed from fibroblasts of symptomatic HD patients (HD-MSNs), which recapitulate adult-onset neurodegenerative pathology of HD, to uncover genes whose reduced function alleviated HD-associated neurodegeneration. We identified RCAN1 whose knockdown (KD) robustly mitigated mutant HTT toxicity. RCAN1 KD enhanced chromatin accessibility of genes involved in longevity and autophagy through promoting Calcineurin and TFEB function. We reveal that G2 compounds, analogs of glibenclamide with autophagy enhancer activities, can mimic the RCAN1 KD-mediated neuroprotection by reducing the RCAN1-Calcineurin interaction, thereby promoting dephosphorylation and nuclear localization of TFEB. Our results indicate RCAN1 as a potential therapeutic target whose perturbation can increase neuronal resilience against neurodegeneration in HD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE210996 | GEO | 2023/08/07

REPOSITORIES: GEO

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Longitudinal modeling of human neuronal aging reveals the contribution of the RCAN1-TFEB pathway to Huntington's disease neurodegeneration

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