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Alpha-synuclein mutations mislocalize cytoplasmic p300 compromising autophagy, which is rescued by ACLY inhibition

1 month 2 weeks ago
Triplications and certain point mutations in the SNCA gene, encoding alpha-synuclein (α-Syn), cause Parkinson's disease (PD). Here, we demonstrate that the PD-causing A53T α-Syn mutation and elevated α-Syn expression perturb acetyl-coenzyme A (CoA) and p300 biology in human neurons and in the CNS of zebrafish and mice. This dysregulation is mediated by activation of ATP-citrate lyase (ACLY), a key enzyme that generates acetyl-CoA in the cytoplasm, via two mechanisms. First, ACLY activity...
Sung Min Son

The mammalian longevity associated acetylome

1 month 2 weeks ago
Despite extensive studies at the genomic, transcriptomic and metabolomic levels, the underlying mechanisms regulating longevity are incompletely understood. Post-translational protein acetylation is suggested to regulate aspects of longevity. To further explore the role of acetylation, we develop the PHARAOH computational tool based on the 100-fold differences in longevity within the mammalian class. Analyzing acetylome and proteome data across 107 mammalian species identifies 482 and 695...
S Feldman-Trabelsi

The retrotransposon-derived capsid genes PNMA1 and PNMA4 maintain reproductive capacity

1 month 2 weeks ago
Almost half of the human genome consists of retrotransposons-'parasitic' sequences that insert themselves into the host genome via an RNA intermediate. Although most of these sequences are silenced or mutationally deactivated, they can present opportunities for evolutionary innovation: mutation of a deteriorating retrotransposon can result in a gene that provides a selective advantage to the host in a process termed 'domestication'^(1-3). The PNMA family of gag-like capsid genes was domesticated...
Thomas W P Wood

40 Hz sensory stimulation enhances CA3-CA1 coordination and prospective coding during navigation in a mouse model of Alzheimer's disease

1 month 2 weeks ago
40 Hz sensory stimulation ("flicker") has emerged as a new technique to potentially mitigate pathology and improve cognition in mouse models of Alzheimer's disease (AD) pathology. However, it remains unknown how 40 Hz flicker affects neural codes essential for memory. Accordingly, we investigate the effects of 40 Hz flicker on neural representations of experience in the hippocampus of the 5XFAD mouse model of AD by recording 1,000s of neurons during a goal-directed spatial navigation task. We...
Abigail L Paulson

AI-Driven Identification of Exceptionally Efficacious Polypharmacological Compounds That Extend the Lifespan of Caenorhabditis elegans

1 month 2 weeks ago
Analysis of existing lifespan-extending geroprotective compounds suggested that polypharmacological compounds are the most effective geroprotectors, specifically those that bind multiple biogenic amine receptors. To test this hypothesis, we used graph neural networks to predict polypharmacological geroprotectors and evaluated them in Caenorhabditis elegans. Over 70% of the selected compounds extended lifespan, with effect sizes in the top 5% compared to all geroprotectors recorded in the DrugAge...
Konstantin Avchaciov

Werner syndrome exonuclease promotes gut regeneration and causes age-associated gut hyperplasia in Drosophila

1 month 2 weeks ago
Human Werner syndrome (adult progeria, a well-established model of human aging) is caused by mutations in the Werner syndrome (WRN) gene. However, the expression patterns and functions of WRN in natural aging remain poorly understood. Despite the link between WRN deficiencies and progeria, our analyses of human colon tissues, mouse crypts, and Drosophila midguts revealed that WRN expression does not decrease but rather increases in intestinal stem cells (ISCs) with aging. Mechanistically, we...
Kun Wu

At the Nexus Between Epigenetics and Senescence: The Effects of Senolytic (BI01) Administration on DNA Methylation Clock Age and the Methylome in Aged and Regenerated Skeletal Muscle

1 month 2 weeks ago
Senescent cells emerge with aging and injury. The contribution of senescent cells to DNA methylation age (DNAmAGE) in vivo is uncertain. Furthermore, stem cell therapy can mediate "rejuvenation", but how tissue regeneration controlled by resident stem cells affects whole tissue DNAmAGE is unclear. We assessed DNAmAGE with or without senolytics (BI01) in aged male mice (24-25 months) 35 days following muscle healing (BaCl(2)-induced regeneration versus non-injured). Young injured mice (5-6...
Toby L Chambers