Biology subjects

Duangjan, C.

Publications and source records attributed to Duangjan, C..

4 recordsLinked to original sources

bioRxiv2024

Oolonghomobisflavans from Camellia sinensis disaggregate tau fibrils across Alzheimer's disease models

Alzheimers disease (AD) is a common debilitating neurodegenerative disease with limited treatment options. Amyloid-{beta} (A{beta}) and tau fibrils are well-established hallmarks of AD, which can induce oxidative stress, neuronal cell death, and are linked to disease pathology. Here, we describe the effects of Oolonghomobisflavan A (OFA) and Oolonghomobisflavan B (OFB) on tau fibril disaggregation and prionogenic seeding. Transcriptomic analysis of OF-treated animals reveals the induction of a proteostasis-enhancing and health-promoting signature. OFA treatment reduced the burden of Tau protein aggregation in a C. elegans model expressing pathogenic human tau ("hTau-expressing") and promoted Tau disaggregation and inhibited seeding in assays using ex vivo brain-derived paired helical filament tau protein fibrils from Alzheimers disease brain donors. Correspondingly, treatment with OF improved multiple fitness and aging-related health parameters in the hTau-expressing C. elegans model, including reproductive output, muscle function, and importantly, reversed the shortened lifespan stemming from pathogenic Tau expression. Collectively, this study provides new evidence supporting the neuroprotective effects of OFs and reveal a new therapeutic strategy for targeting AD and other neurodegenerative diseases characterized by tauopathy.

physiology↗

bioRxiv2023

WDR23 mediates NRF2 proteostasis and cytoprotective capacity in the hippocampus

Pathogenic brain aging and neurodegenerative diseases such as Alzheimers disease and Parkinsons disease are characterized by chronic neuroinflammation and the accumulation of dysfunctional or misfolded proteins that lead to progressive neuronal cell death. Here we demonstrate that a murine model with global loss of the CUL4-DDB1 substrate receptor WDR23 (Wdr23KO) results in changes in multiple age-related hippocampal-dependent behaviors. The behavioral differences observed in Wdr23KO animals accompany the stabilization of the NRF2/NFE2L2 protein, an increase in RNA transcripts regulated by this cytoprotective transcription factor, and an increase in the steady state level of antioxidant defense proteins. Taken together, these findings reveal a role for WDR23-proteostasis in mediating cytoprotective capacity in the hippocampus and reveal the potential for targeting WDR23-NRF2 signaling interactions for development of therapies for neurodegenerative disorders. HIGHLIGHTSO_LIWDR23 regulates NRF2/NFE2L2 stability in the mouse hippocampus C_LIO_LILoss of Wdr23 significantly increases the expression of NFE2L2/NRF2 target genes C_LIO_LIGlobal loss of WDR23 influences age-related behaviors differentially in males and females C_LI

molecular biology↗

bioRxiv2023

Loss of Wdr23 drives neuronal mitochondrial biogenesis

Mitochondrial adaptation is important for stress resistance throughout life. Here we show that WDR23 loss results in an enrichment for genes regulated by nuclear respiratory factor 1 (NRF1), which coordinates mitochondrial biogenesis and respiratory functions, and an increased steady state level of nuclear coded mitochondrial resident proteins in the brain. Wdr23KO also increases the endogenous levels of insulin degrading enzyme (IDE) and the relaxin-3 peptide (RLN3), both of which mediate mitochondrial metabolic and oxidative stress responses. Taken together, these studies reveal an important role for WDR23 as a component of the mitochondrial homeostat in the murine brain. HIGHLIGHTSO_LILoss of Wdr23 increases nuclear-coded mitochondrial resident proteins. C_LIO_LIPromoters of transcripts dysregulated in the hippocampus of Wdr23KO mice are enriched for NRF1 regulatory sequences. C_LIO_LIInsulin degrading enzyme (IDE) expression, which can localize to the mitochondria, is increased in the brain tissues lacking WDR23. C_LIO_LIWdr23KO animals have increased expression of relaxin-3 (RLN3) peptide, but not RLFP3 receptor. C_LI

molecular biology↗

bioRxiv2022

Hepatic WDR23 proteostasis mediates insulin clearance by regulating insulin degrading enzyme activity

Clearance of circulating insulin is critical for metabolic homeostasis. In the liver, insulin is degraded by the activity of the insulin-degrading enzyme (IDE). Here we establish a hepatic regulatory axis for IDE through WDR23-proteostasis. Wdr23KO mice have increased IDE expression, reduced circulating insulin, and defective insulin responses. Genetically engineered human cell models lacking WDR23 also increase IDE expression and display dysregulated phosphorylation of insulin signaling cascade proteins, IRS-1, AKT2, MAPK, FoxO, and mTOR, similar to cells treated with insulin, which can be mitigated by chemical inhibition of IDE. Mechanistically, the cytoprotective transcription factor NRF2, a direct target of WDR23-Cul4 proteostasis, mediates the enhanced transcriptional expression of IDE when WDR23 is ablated. Moreover, an analysis of human genetic variation in WDR23 across a large naturally aging human cohort in the US Health and Retirement Study reveals a significant association of WDR23 with altered hemoglobin A1C (HbA1c) levels in older adults, supporting the use of WDR23 as new molecular determinant of metabolic health in humans.

cell biology↗