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Integrative determination of atomic structure of mutant huntingtin exon 1 fibrils implicated in Huntington disease

6 months ago
Neurodegeneration in Huntington's disease (HD) is accompanied by the aggregation of fragments of the mutant huntingtin protein, a biomarker of disease progression. A particular pathogenic role has been attributed to the aggregation-prone huntingtin exon 1 (HTTex1), generated by aberrant splicing or proteolysis, and containing the expanded polyglutamine (polyQ) segment. Unlike amyloid fibrils from Parkinson's and Alzheimer's diseases, the atomic-level structure of HTTex1 fibrils has remained...
Mahdi Bagherpoor Helabad

Photoswitch dissociation from a G protein-coupled receptor resolved by time-resolved serial crystallography

6 months ago
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors in humans. The binding and dissociation of ligands tunes the inherent conformational flexibility of these important drug targets towards distinct functional states. Here we show how to trigger and resolve protein-ligand interaction dynamics within the human adenosine A(2A) receptor. For this, we designed seven photochemical affinity switches derived from the anti-Parkinson's drug istradefylline. In a rational...
Hannah Glover

A high-protein diet-responsive gut hormone regulates behavioral and metabolic optimization in Drosophila melanogaster

6 months ago
Protein is essential for all living organisms; however, excessive protein intake can have adverse effects, such as hyperammonemia. Although mechanisms responding to protein deficiency are well-studied, there is a significant gap in our understanding of how organisms adaptively suppress excessive protein intake. In the present study, utilizing the fruit fly, Drosophila melanogaster, we discover that the peptide hormone CCHamide1 (CCHa1), secreted by enteroendocrine cells in response to a...
Yuto Yoshinari

A microbiota-derived metabolite, 3-phenyllactic acid, prolongs healthspan by enhancing mitochondrial function and stress resilience via SKN-1/ATFS-1 in C. elegans

6 months ago
The mechanisms underlying the impact of probiotic supplementation on health remain largely elusive. While previous studies primarily focus on the discovery of novel bioactive bacteria and alterations in the microbiome environment to explain potential probiotic effects, our research delves into the role of living Lactiplantibacillus (formerly known as Lactobacillus) and their conditioned media, highlighting that only the former, not dead bacteria, enhance the healthspan of Caenorhabditis elegans...
Juewon Kim

Higher skeletal muscle mitochondrial oxidative capacity is associated with preserved brain structure up to over a decade

6 months ago
Impaired muscle mitochondrial oxidative capacity is associated with future cognitive impairment, and higher levels of PET and blood biomarkers of Alzheimer's disease and neurodegeneration. Here, we examine its associations with up to over a decade-long changes in brain atrophy and microstructure. Higher in vivo skeletal muscle oxidative capacity via MR spectroscopy (post-exercise recovery rate, k(PCr)) is associated with less ventricular enlargement and brain aging progression, and less atrophy...
Qu Tian

Hidden route of protein damage through oxygen-confined photooxidation

6 months ago
Oxidative modifications can disrupt protein folds and functions, and are strongly associated with human aging and diseases. Conventional oxidation pathways typically involve the free diffusion of reactive oxygen species (ROS), which primarily attack the protein surface. Yet, it remains unclear whether and how internal protein folds capable of trapping oxygen (O(2)) contribute to oxidative damage. Here, we report a hidden pathway of protein damage, which we refer to as O(2)-confined...
Seoyoon Kim

Aging-induced immune microenvironment remodeling fosters melanoma in male mice via gammadelta17-Neutrophil-CD8 axis

6 months ago
Aging is associated with increased tumor metastasis and poor prognosis. However, how an aging immune system contributes to the process is unclear. Here, single-cell RNA sequencing reveals that in male mice, aging shifts the lung immune microenvironment towards a premetastatic niche, characterized by an increased proportion of IL-17-expressing γδT (γδ17) and neutrophils. Mechanistically, age-dependent downregulation of the immune trafficking receptor S1pr1 drives the expansion of γδ17. Compared...
Runping Duan

GATD3A-deficiency-induced mitochondrial dysfunction facilitates senescence of fibroblast-like synoviocytes and osteoarthritis progression

6 months ago
Accumulating evidence indicates that cellular senescence is closely associated with osteoarthritis. However, there is limited research on the mechanisms underlying fibroblast-like synoviocyte senescence and its impact on osteoarthritis progression. Here, we elucidate a positive correlation between fibroblast-like synoviocyte senescence and osteoarthritis progression and reveal that GATD3A deficiency induces fibroblast-like synoviocyte senescence. Mechanistically, GATD3A deficiency enhances the...
Kai Shen

Age-dependent regulation of axoglial interactions and behavior by oligodendrocyte AnkyrinG

6 months ago
The bipolar disorder (BD) risk gene ANK3 encodes the scaffolding protein AnkyrinG (AnkG). In neurons, AnkG regulates polarity and ion channel clustering at axon initial segments and nodes of Ranvier. Disruption of neuronal AnkG causes BD-like phenotypes in mice. During development, AnkG is also expressed at comparable levels in oligodendrocytes and facilitates the efficient assembly of paranodal junctions. However, the physiological roles of glial AnkG in the mature nervous system, and its...
Xiaoyun Ding

Evaluation of the effects of thyroid functions on frailty in geriatric patients using the Edmonton, SOF and FRAIL Scales

6 months ago
CONCLUSION: This study highlights the significant impact of thyroid dysfunction on frailty in older adults. Lower fT3 levels and the fT3/fT4 ratio emerged as key indicators of increased frailty, particularly on the SOF and EFS scales. Subgroup analysis further emphasized the importance of age-specific assessments, with a lower fT3/fT4 ratio being a critical indicator of frailty in individuals aged ≥ 80 years, while lower TSH levels were significant in those aged < 80 years. Abnormal TSH levels...
Galip Can Uyar