Biology subjects

Tan, E. K.

Publications and source records attributed to Tan, E. K..

4 recordsLinked to original sources

bioRxiv2025

Mitoxantrone Hydrochloride Targets APP and LRRK2 to Improve Neurodegeneration in Parkinson's Models

BackgroundParkinsons disease (PD) is the second common neurodegenerative disorder, driven by the loss of dopaminergic neurons and pathological -synuclein protein accumulation. Currently, there is no disease-modifying therapy that can halt PD progression. Our previous study uncovered a critical pathogenic feed-forward loop between amyloid precursor protein (APP) and leucine-rich repeat kinase 2 (LRRK2), in which the two proteins mutually enhance each others expression, ultimately leading to mitochondrial dysfunction and neurotoxicity. Targeting this vicious cycle represents a promising therapeutic strategy for PD. MethodsTo discover novel inhibitors targeting this axis, we performed high-throughput screening of an FDA-approved drug library using a fluorescence-based biosensor system. We identified Mitoxantrone hydrochloride (MH), an antineoplastic agent, as a lead compound that inhibits both APP and LRRK2 expression. Its efficacy was validated in cellular models, including patient induced pluripotent stem cell (iPSC)-derived dopaminergic neurons and human peripheral blood mononuclear cells (PBMCs). Motor behavioural and safety assessments were subsequently conducted in PD mouse models. ResultsWe demonstrated that MH suppresses both APP and LRRK2 expression in various cell types in a dosage-dependent manner. In addition, MH also inhibits phosphorylation of LRRK2 and its downstream substrate Rab10. We further showed MH inhibits LRRK2 activity through direct binding to its kinase domain. Critically, MH treatment rescued dopaminergic neuron loss and reversed motor deficits in both 6-Hydroxydopamine (6-OHDA)-induced and LRRK2G2019S genetic PD mouse models. Moreover, we found that oral administration of MH is therapeutically effective, providing superior neuroprotection and behavioral recovery without detectable cardiotoxicity or gastrointestinal damage. ConclusionsOur findings demonstrate MH as a compelling, repurposable therapeutic candidate capable of disrupting a core pathogenic mechanism in PD.

neuroscience↗

bioRxiv2024

Cyclin O controls entry into the cell-cycle variant required for multiciliated cell differentiation

Multiciliated cells (MCC) ensure proper fluid circulation in various organs in metazoans. Their differentiation is marked by the massive ampliication of cilia-nucleating centrioles and is known to be controlled by various cell cycle components. Tn a companion study, we show that the differentiation of MCC is driven by a genuine cell-cycle variant characterized by sequential and wave-like expression of canonical and non-canonical cyclins such as Cyclin O (CCNO). Patients with CCNO mutations exhibit a subtype of Primary Ciliary Dyskinesia (PCD) designated as Reduced Generation of Multiple Motile Cilia (RGMC), yet the role of CCNO during MCC differentiation remains unclear. Here, using mice and human cellular models, single cell transcriptomics and functional studies, we show that Cena is activated during a strategic temporal window at the crossroads between the onset of MCC differentiation, the entry into the MCC cell cycle variant, and the activation of the centriole biogenesis program. We ind that the absence of Cena leads to a block of MCC progenitor differentiation at the G1/S-like transition, just before the beginning of centriole formation. This leads to a complete lack of centrioles and cilia in mouse brain and human airway MCC. Altogether, our study identifies CCNO as a core regulator of entry into the MCC cell cycle variant and shows that the coupling of centriole biogenesis to an S-like phase, maintained in MCC, is dependent on CCNO. One sentence summaryCyclin O is necessary for multiciliated cells to enter their differentiation cell cycle variant and allows the massive amplification of centrioles, which serve as basal bodies for cilia nucleation.

cell biology↗

bioRxiv2024

Hosts Manipulate Lifestyle Switch and Pathogenicity Heterogeneity of Opportunistic Pathogens in the Single-cell Resolution

Host-microbe interactions are virtually bidirectional, but how the host affects their microbiome is poorly understood. Here, we report that the host is a critical modulator to regulate the lifestyle switch and pathogenicity heterogeneity of the opportunistic pathogens Serratia marcescens utilizing the Drosophila and bacterium model system. First, we find that Drosophila larvae efficiently outcompete S. marcescens and typically drive a bacterial switch from pathogenicity to commensalism toward the fly. Furthermore, Drosophila larvae reshape the transcriptomic and metabolic profiles of S. marcescens characterized by a lifestyle switch. More important, the host alters pathogenicity and heterogeneity of S. marcescens in the single-cell resolution. Finally, we find that larvae-derived AMPs are required to recapitulate the response of S. marcescens to larvae. Altogether, our findings provide an insight into the pivotal roles of the host in harnessing the life history and heterogeneity of symbiotic bacterial cells, advancing knowledge of the reciprocal relationships between the host and pathogen.

microbiology↗

bioRxiv2021

Mutated in Colorectal Cancer (MCC): a centrosomal protein that relocalizes to the ncMTOC during intestinal cell differentiation

Mutated in Colorectal Cancer (MCC) encodes a coiled-coil protein implicated, as its name suggests, in the pathogenesis of hereditary human colon cancer. To date, however, the contributions of MCC to intestinal homeostasis remain unclear. Here, we examine the subcellular localization of MCC, both at the mRNA and protein levels, in the adult intestinal epithelium. Our findings reveal that Mcc transcripts are restricted to proliferating crypt cells, including Lgr5+ stem cells, and that Mcc protein is distinctly associated with the centrosome in these cells. Upon intestinal cellular differentiation, Mcc is redeployed to the non-centrosomal microtubule organizing center (ncMTOC) at the apical domain of villus cells. Using intestinal organoids, we show that the shuttling of the Mcc protein depends on phosphorylation by Casein Kinases 1{delta}/{varepsilon}, which are critical modulators of WNT signaling. Together, our findings support a putative role for MCC in establishing and maintaining the cellular architecture of the intestinal epithelium as a component of both the centrosome and ncMTOC.

cell biology↗