Biology subjects

Wong, S. H.

Publications and source records attributed to Wong, S. H..

3 recordsLinked to original sources

bioRxiv2024

Functional and multi-omic aging rejuvenation with GLP-1R agonism

Identifying readily implementable methods that can effectively counteract aging is urgently needed for tackling age-related degenerative disorders. Here, we conducted functional assessments and deep molecular phenotyping in the aging mouse to demonstrate that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment attenuates body-wide age-related changes. Apart from improvements in physical and cognitive performance, the age-counteracting effects are prominently evident at multiple omic levels. These span the transcriptomes and DNA methylomes of various tissues, organs and circulating white blood cells, as well as the plasma metabolome. Importantly, the beneficial effects are specific to aged mice, not young adults, and are achieved with a low dosage of GLP-1RA which has a negligible impact on food consumption and body weight. The molecular rejuvenation effects exhibit organ-specific characteristics, which are generally heavily dependent on hypothalamic GLP-1R. We benchmarked the GLP-1RA age-counteracting effects against those of mTOR inhibition, a well-established anti-aging intervention, observing a strong resemblance across the two strategies. Our findings have broad implications for understanding the mechanistic basis of the clinically observed pleiotropic effects of GLP-1RAs, the design of intervention trials for age-related diseases, and the development of anti-aging-based therapeutics.

systems biology↗

bioRxiv2023

Fluorescent Peptide-based Probe for the Detection of Alpha-synuclein Aggregates in the Gut

BackgroundParkinsons disease (PD) is diagnosed clinically by motor symptoms, with no molecular diagnostic test currently available. By the time motor symptoms manifest, significant irreversible neurodegeneration has already occurred, limiting the effectiveness of neuroprotective therapies and drug interventions. Recent identification of pathological alpha-synuclein (-syn) aggregates in the gastrointestinal (GI) tract of prodromal PD patients offer a potential avenue for early disease diagnosis. This study aims to explore specific fluorescence labelling of -syn aggregates in the GI tract using a peptide-based probe for early diagnosis of PD. MethodsWe used primary hippocampal neuronal cells and wild-type mouse tissues with the addition of pre-formed -syn fibrils to identify the most suitable peptide fluorescent probe (P1) for staining -syn aggregates in cells and tissues. We validated the probe labelling in GI tract tissues from three mouse models, including PFF-injected mice and two transgenic PD mouse strains. We quantified labelling accuracy by confocal imaging and protein analysis. ResultsWe found that P1 labelled -syn aggregates with high accuracy (87% in comparison to Serine129-phosphorylated -syn antibody) and high specificity for labelling their aggregated forms over monomeric forms. In GI tract tissues, P1 labelled -syn aggregates across tissue layers (mucosa, sub-mucosa, muscularis externa) and achieved comparable performance to antibody staining. Higher degree of probe labelling was found in older mice due to increased accumulation of -syn aggregates with ageing. Notably, -syn aggregates were readily detectable in the colonic mucosae using P1, indicating the potential use of this probe for early PD diagnosis during colonic examinations like colonoscopy. ConclusionWe have developed a peptide-based fluorescent probe and demonstrated its rapid and specific labelling of -syn aggregates. We highlight the probes ability to label these aggregates rapidly over -syn monomers and survey the abundance of -syn aggregates throughout the entire length of the GI tract. These support the further development of P1 as a specific fluorescent imaging biomarker for colonic -syn aggregates for the early detection of PD.

neuroscience↗

bioRxiv2023

In silico MS/MS prediction for peptidoglycan profiling uncovers novel anti-inflammatory peptidoglycan fragments of the gut microbiota

Peptidoglycan is an essential exoskeletal polymer present across all bacteria. The gut microbiota-derived peptidoglycan fragments (PGNs) are increasingly recognized as key effector molecules that impact host biology, offering attractive yet untapped potential to combat microbiome-associated diseases in humans. Unfortunately, comprehensive peptidoglycan profiling of gut bacteria has been hampered by the lack of a robust and automated analysis workflow. Currently, PGN identification still relies on manual deconvolutions of acquired tandem mass spectrometry (MS/MS) data, which are highly laborious and inconsistent. Recognizing the unique sugar and amino acid makeup of bacterial peptidoglycan and guided by the experimental MS/MS fragmentation patterns of known PGNs, we developed a computational tool PGN_MS2 that reliably simulates MS/MS spectra of PGNs. Integrating PGN_MS2 into the customizable in silico PGN database, we built an open-access PGN MS library of predicted MS/MS spectra for all molecules in the user-defined in silico PGN search space. With this library, automated searching and spectral matching can be used to identify PGN. We then performed comprehensive peptidoglycan profiling for several gut bacteria species, revealing distinct PGN structural features that may be implicated in microbiota-host crosstalk. Strikingly, the probiotic Bifidobacterium spp. has an exceedingly high proportion of anhydro-PGNs, which exhibit anti-inflammatory effects in vitro. We further identified MltG and RfpB homologs in Bifidobacterium as lytic transglycosylases (LTs), which demonstrate distinct substrate preferences to produce anhydro-PGNs. Overall, our novel PGN_MS2 prediction tool contributes to the robust and automated peptidoglycan analysis workflow, advancing efforts to elucidate the structures and functions of gut microbiota-derived PGNs in the host.

microbiology↗