Biology subjects

Irwin, R.

Publications and source records attributed to Irwin, R..

4 recordsLinked to original sources

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

Exercise rejuvenates the skeletal muscle methylome and transcriptome in humans

Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta-analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle samples (n = 3,176). We show that: 1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, 2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns towards a younger profile, and 3) muscle disuse "ages" the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted towards a younger state after exercise training interventions, while the transcriptome shifted towards an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age-related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity.

molecular biology↗

bioRxiv2021

Hsp40s display class-specific binding profiles, serving complementary roles in the prevention of tau amyloid formation

The microtubule-associated protein, tau, is the major subunit of neurofibrillary tangles, forming insoluble, amyloid-type aggregates associated with neurodegenerative conditions, such as Alzheimers disease. Tau aggregation, however, can be prevented in the cell by a class of proteins known as molecular chaperones, which play important roles in maintaining protein homeostasis. While numerous chaperones are known to interact with tau, though, little is known about the detailed mechanisms by which these prevent tau aggregation. Here, we describe the effects of the ATP-independent Hsp40 chaperones, DNAJA2 and DNAJB1, on tau amyloid fiber formation and compare these to the well-studied small heat shock protein HSPB1. We find that each chaperone prevents tau aggregation differently, by interacting with distinct sets of tau species along the aggregation pathway and thereby affecting their incorporation into fibers. Whereas HSPB1 only binds tau monomers, DNAJB1 and DNAJA2 recognize aggregation-prone tau conformers and even mature fibers, thus efficiently preventing formation of tau amyloids. In addition, we find that both Hsp40s bind tau seeds and fibers via their C-terminal domain II (CTDII), with DNAJA2 being further capable of recognizing tau monomers by a second, different site in CTDI. These results provide important insight into the molecular mechanism by which the different members of the Hsp40 chaperone family counteract the formation, propagation, and toxicity of tau aggregates. Furthermore, our findings highlight the fact that chaperones from different families and different classes play distinct, but complementary roles in preventing pathological protein aggregation.

biophysics↗