Biology subjects

Yeung, S. H.-S.

Publications and source records attributed to Yeung, S. H.-S..

3 recordsLinked to original sources

bioRxiv2025

Nuclear BIN1 isoforms regulate c-Myc-mediated cell cycle control in oligodendrocytes

Bridging integrator 1 (BIN1) is a nucleocytoplasmic protein that inhibits c-Myc and acts as a tumour suppressor. BIN1 is ubiquitously expressed, but it is most abundant in skeletal myocytes and brain oligodendrocytes (OLs). BIN1 expression in the OL lineage is of particular interest, as the loss of myelin integrity is highly correlated with the progress of sporadic AD. More importantly, GWAS studies have identified rare BIN1 variants as the second strongest risk factor for sporadic Alzheimers disease (AD), after the {varepsilon}4 variant of APOE gene. Despite these inherent interests, the control of the nucleocytoplasmic localisation as well as the modulation of the alternative splicing of the 20 exons of BIN1 are poorly understood in OLs. We report here the characterisation of BIN1 isoforms in OLs from two independent cohorts of postmortem AD brains using immunoblotting and immunohistochemistry and extend the findings to experimental APP/PS1 mice and primary murine OL cultures. Neuronal isoforms of BIN1 (BIN1:H, 95kDa) were significantly reduced (P < 0.0001), and the white matter/OL-specific isoforms (BIN1:L, 70kDa) were increased (P = 0.0349) in both AD cases and APP/PS1 mice. Importantly, the OL-specific BIN1 isoforms, identified by three different antibodies, were found in the nucleus of OL in human and mouse. Nuclear BIN1 was expressed by both the OL progenitor cells (OPCs) and mature OLs in vitro. Silencing Bin1 in OPCs led to a transcriptomic shift with a perturbed p53 pathway and cell cycle regulation, consistent with reduced Bin1-mediated c-Myc inhibition. The putative interacting sites between OL-specific BIN1:L and c-Myc were also identified by in silico analysis. The present findings suggest that nuclear BIN1 acts as a regulator of OL cell cycle control and support the hypothesis that BIN1 dysregulation in OL may contribute mechanistically to myelin pathology observed in sporadic AD.

cell biology↗

bioRxiv2023

White matter hyperintensity genetic risk factor TRIM47 regulates autophagy in brain endothelial cells

White matter hyperintensity (WMH) is strongly correlated with age-related dementia and hypertension, but its pathogenesis remains obscure. GWAS identified TRIM47 at 17q25 locus as a top genetic risk factor for WMH formation. TRIM family is a class of E3 ubiquitin ligase with pivotal functions in autophagy, which is critical for brain endothelial cell (ECs) remodeling during hypertension. We hypothesize that TRIM47 regulates autophagy and its loss-of-function disturbs cerebrovasculature. Based on transcriptomics and immunohistochemistry, TRIM47 is found selectively expressed by brain ECs in human and mouse, and its transcription is upregulated by artificially-induced autophagy while downregulated in hypertension-like conditions. Using in silico simulation, immunocytochemistry and super-resolution microscopy, we identified the highly conserved binding site between TRIM47 and the LIR (LC3-interacting region) motif of LC3B. Importantly, pharmacological autophagy induction increased Trim47 expression on mouse ECs (b.End3) culture, while silencing Trim47 significantly increased autophagy with ULK1 phosphorylation induction, transcription and vacuole formation. Together, we confirm that TRIM47 is an endogenous inhibitor of autophagy in brain ECs, and such TRIM47-mediated regulation connects genetic and physiological risk factors for WMH formation but warrants further investigation. SUMMARY STATEMENTTRIM47, top genetic risk factor for white matter hyperintensity formation, is a negative regulator of autophagy in brain endothelial cells and implicates a novel cellular mechanism for age-related cerebrovascular changes.

cell biology↗

bioRxiv2023

Cuprizone drives divergent neuropathological changes in different mouse models of Alzheimer's disease

Myelin degradation is a normal feature of brain aging that accelerates in Alzheimers disease (AD). To date, however, the underlying biological basis of this correlation remains elusive. The amyloid cascade hypothesis predicts that demyelination is caused by increased levels of the {beta}-amyloid (A{beta}) peptide. Here we report on work supporting the alternative hypothesis that early demyelination is upstream of amyloid. We challenged two different mouse models of AD (R1.40 and APP/PS1) using cuprizone-induced demyelination and tracked the responses with both neuroimaging and neuropathology. In oppose to amyloid cascade hypothesis, R1.40 mice, carrying only a single human mutant APP (Swedish; APPSWE) transgene, showed a more abnormal changes of magnetization transfer ratio and diffusivity than in APP/PS1 mice, which carry both APPSWE and a second PSEN1 transgene (delta exon 9; PSEN1dE9). Although cuprizone targets oligodendrocytes (OL), magnetic resonance spectroscopy and targeted RNA-seq data in R1.40 mice suggested a possible metabolic alternation in axons. In support of alternative hypotheses, cuprizone induced significant intraneuronal amyloid deposition in young APP/PS1, but not in R1.40 mice, and it suggested the presence of PSEN deficiencies, may accelerate A{beta} deposition upon demyelination. In APP/PS1, mature OL is highly vulnerable to cuprizone with significant DNA double strand breaks (53BP1+) formation. Despite these major changes in myelin, OLs, and A{beta} immunoreactivity, no cognitive impairment or hippocampal pathology was detected in APP/PS1 mice after cuprizone treatment. Together, our data supports the hypothesis that myelin loss can be the cause, but not the consequence, of AD pathology. SIGNIFICANCE STATEMENTThe causal relationship between early myelin loss and the progression of Alzheimers disease remains unclear. Using two different AD mouse models, R1.40 and APP/PS1, our study supports the hypothesis that myelin abnormalities are upstream of amyloid production and deposition. We find that acute demyelination initiates intraneuronal amyloid deposition in the frontal cortex. Further, the loss of oligodendrocytes, coupled with the accelerated intraneuronal amyloid deposition, interferes with myelin tract diffusivity at a stage before any hippocampus pathology or cognitive impairments occur. We propose that myelin loss could be the cause, not the consequence, of amyloid pathology during the early stages of Alzheimers disease.

neuroscience↗