Biology subjects

Lau, P. Y.

Publications and source records attributed to Lau, P. Y..

3 recordsLinked to original sources

bioRxiv2025

Loss of HMGCS2-mediated intestinal stem cell ketogenesis is a metabolic barrier to mucosal healing in Ulcerative colitis

Human colonic epithelial cells express high levels of 3-Hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), the crucial mitochondrial enzyme responsible for the production ketone bodies, predominantly beta-hydroxybutyrate ({beta}HB). Ketogenesis is an important metabolic pathway responsible for energy production in states of fasting and in the intestine ketone bodies are also important in regulating intestinal stem cell (ISC) homeostasis and regeneration. Using combined single-cell and spatial transcriptomics, organoids and prospective longitudinal mucosal analysis, we demonstrated a profound loss of ISC HMGCS2-mediated ketogenesis with consequential detrimental effect on Ulcerative colitis (UC), a chronic inflammatory bowel disease that affects [~]4 million individuals worldwide. We show that {beta}HB restores UC ISC metabolic function, reduces cellular stress with further evidence of epigenetic programming key for restoration of ISC function. Furthermore, low colonic HMGCS2 expression is associated with treatment failure of multiple biological immune therapies in UC. Our findings reveal the crucial role for HMGCS2 and loss of ketogenesis as the tipping point for pathogenic epithelial dysfunction and importantly, a promising metabolic therapeutic target for UC.

cell biology↗

bioRxiv2021

Protist.guru: a comparative transcriptomics database for the protist kingdom

SummaryDuring the last few decades, the study of microbial ecology has been enabled by molecular and genomic data. DNA sequencing has revealed the surprising extent of microbial diversity and how microbial processes run global ecosystems. However, significant gaps in our understanding of the microbial world remain, and one example is that microbial eukaryotes, or protists, are still neglected. To address this gap, we used gene expression data from 15 distinct protist species to create protist.guru: an online database equipped with tools for identifying functional co-expression networks, gene families, and enriched gene clusters. Here, we show how our database can be used to reveal genes involved in essential pathways, such as the synthesis of secondary carotenoids in Haematococcus lacustris. We expect protist.guru to serve as a valuable resource for protistologists, as well as a catalyst for discoveries and new insights into the biological processes of microbial eukaryotes. AvailabilityThe database and co-expression networks are freely available from http://protist.guru/. The expression matrices and sample annotations are found in the supplementary data.

evolutionary biology↗

bioRxiv2018

Loss of Frrs1l disrupts synaptic AMPA receptor function, and results in neurodevelopmental, motor, cognitive and electrographical abnormalities

Summary statementIn this study, we show that the loss of the epilepsy-related gene Frrs1l in mice causes a dramatic reduction in AMPA receptor levels at the synapse. This change elicits severe motor and coordination disabilities, hyperactivity, cognitive defects, behavioural seizures and abnormal electroencephalographic (EEG) patterns.\n\nAbstractLoss of function mutations in the human AMPA receptor-associated protein, ferric chelate reductase 1-like (FRRS1L), are associated with a devastating neurological condition incorporating choreoathetosis, cognitive deficits and epileptic encephalopathies. Furthermore, evidence from overexpression and ex vivo studies have implicated FRRS1L in AMPA receptor biogenesis and assembly, suggesting that changes in glutamatergic signalling might underlie the disorder. Here, we investigated the neurological and neurobehavioural correlates of the disorder using a mouse Frrs1l null mutant. The study revealed several neurological defects that mirrored those seen in human patients. We established that mice lacking Frrs1l suffered from a broad spectrum of early-onset motor deficits with no progressive, age-related deterioration. Moreover, Frrs1l-/- mice were hyperactive irrespective of test environment, exhibited working memory deficits and displayed significant sleep fragmentation. Longitudinal electroencephalographic recordings also revealed abnormal EEG in Frrs1l-/- mice. Parallel investigations into disease aetiology identified a specific deficiency in AMPA receptor levels in the brain of Frrs1l-/- mice, while the general levels of several other synaptic components remained unchanged with no obvious alterations in the number of synapses. Furthermore, we established that Frrsl1 deletion results in glycosylation deficits in GLUA2 and GLUA4 AMPA receptor proteins, leading to cytoplasmic retention and a reduction of those specific AMPA receptor levels in the postsynaptic membrane. Overall, this study determines, for the first time in vivo, how loss of FRRS1L function can affect glutamatergic signalling and provides mechanistic insight into the development and progression of a human hyperkinetic disorder.

neuroscience↗