Attenuating DNA hypermethylation enhances insulin signaling and reduces apoptosis in an in vitro model of DLB
Chih‐Li Lin, Sing‐Hua Tsou, Chien‐Ning Huang, Ching‐Chi Chang, Ying‐Jui Ho- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Dementia with Lewy bodies (DLB) is the second most prevalent degenerative dementia after Alzheimer’s disease (AD). The cause of DLB is known to be associated with abnormal protein aggregations called Lewy bodies within affected neurons. Studies have shown that Lewy bodies are mainly composed of α‐synuclein. Normal α‐synuclein is a water‐soluble monomer. However, when triggered by certain factors, the folding of the protein changes, causing it to aggregate and accumulate inside neurons. Previously, we have demonstrated that amyloid β (Aβ) can promote α‐synuclein aggregation and neurotoxicity, which provides a molecular mechanism that reasonably explained the pathogenesis of DLB. A major risk factor for DLB is known to be aging, but its role in disease progression, especially with regard to epigenetic regulation, is still unclear.
Method
In this study, we investigated whether DNA hypermethylation, a common phenomenon in cellular aging, might be a factor in the progression of DLB. Through the in vitro experimental mode of DLB, we analyzed the content of α‐synuclein aggregations, the difference in cell viability and the activity changes of methylation‐related pathways in mouse HT‐22 neuronal cells.
Result
We found that the DLB neuronal cells display a significant tendency to undergo DNA hypermethylation, which inhibits stemness and reduces the content of neurotrophic factors. This makes it more difficult for neuronal cells to survive under stress. In addition, DLB neuronal cells also showed significant insulin resistance, which interferes with autophagic clearance, upregulates the senescence‐related pathways, and exacerbates the aggregation and accumulation of α‐synuclein.
Conclusion
DLB cells significantly increase the hypermethylation and thus inhibit insulin signaling, making the affected cells more vulnerable to neurotoxicity. Accordingly, the administration of epigenetic regulators by targeting neuronal DNA hypermethylation may lead to develop novel therapeutic strategies against DLB.