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Receptor transmembrane domains (TMDs) are crucially involved in relaying ligand information from extracellular to intracellular spaces and represent attractive targets for small molecule manipulation of receptor function.

Screening a library of over 8,000 drug-like compounds with an assay based on the TMD of death receptor p75^NTR, we identified a novel small molecule capable of inhibiting p75^NTR-mediated migration of human melanoma cells. Employing medicinal chemistry, a more potent derivative termed Np75-4A22 was identified that blocked nerve growth factor (NGF)-mediated melanoma invasion at sub-micromolar concentrations. The specific interaction of Np75-4A22 with the p75^NTR TMD was confirmed by 2D NMR. Mechanistically, Np75-4A22 was found to antagonize NGF-mediated recruitment of the actin-bundling protein fascin to p75^NTR, fascin association with the actin cytoskeleton and filopodia formation. Importantly, preclinical assessment of Np75-4A22 showed high oral bioavailability, low toxicity, and significant inhibition of melanoma lung invasion in mice.

These results support further development of this approach as an alternative or complementary strategy for melanoma cancer patients that do not respond to conventional chemotherapy or immune checkpoint inhibitors. 

The paper has been published in EMBO Molecular Medicine

GFRα1 and Ret are the two necessary components of the receptor for GDNF, a neurotrophic factor discovered in the early 1990’s for its ability to support the survival of midbrain dopaminergic neurons, including those in the substantia nigra (SN) that project to the dorsal striatum (dSTR) and degenerate in Parkinson’s Disease. Several GDNF clinical trials have been conducted to date with mixed results. Despite the physiological and clinical importance of this signaling system, whether any of its components are required for the maintenance of adult SN neurons has not yet been elucidated.

In this study, we first analyzed postnatal expression patterns of Gfrα1 and Ret in the SN and established that mRNA levels peak at mouse postnatal day 15 (P15), stabilizing after P30. Using Tamoxifen-induced deletion of Gfrα1 at 3 months of age, we found that GFRα1 is required for the maintenance of a subset of adult SN dopaminergic neurons. FluoroGold tracing of SN axons from the dSTR in mutant mice revealed that ablation of GFRα1 preferentially affects the subset of ­ GFRα1-expressing neurons that project to the STR.

In addition to the well-known neuroprotective functions of GDNF/GFRα1/RET signaling, our results establish a physiological requirement of the GFRα1 component of this neurotrophic system for the continuous maintenance of SN dopaminergic neurons in the adult brain.

The paper has been published in PLOS One

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is a major threat to the aging population. Due to lack of effective therapy, preventive treatments are important strategies to limit AD onset and progression, of which dietary regimes have been implicated as a key factor. Diet with high fiber content is known to have beneficial effects on cognitive decline in AD. However, a global survey on microbiome and brain cell dynamics in response to high fiber intake at single-cell resolution in AD mouse models has been unavailable.

In this study, we show that dietary inulin supplementation synergized with AD progression to specifically increase the abundance of Akkermansia muciniphila in gut microbiome of 5 × Familial AD (FAD) mice. By performing single-nucleus RNA sequencing on different regions of the whole brain with three independent biological replicates, we reveal region-specific changes in the proportion of neuron, astrocyte, and granule cell subpopulations upon inulin supplementation in 5xFAD mice. In addition, we find that astrocytes have more pronounced region-specific diversity than microglia. Intriguingly, such dietary change reduces amyloid-β plaque burden and alleviates microgliosis in the forebrain region, without affecting the spatial learning and memory.

These results provide a comprehensive overview on the transcriptomic changes in individual cells of the entire mouse brain in response to high fiber intake and a resourceful foundation for future mechanistic studies on the influence of diet and gut microbiome on the brain during neurodegeneration.

The paper has been published in BMC Biology

The capacity of mature adipocytes to de-differentiate into fibroblast-like cells has been demonstrated in vitro and a few, rather specific in vivo conditions. A detailed comparison between de-differentiated fat (DFAT) cells and adipose stem and progenitor cells (ASPCs) from different adipose depots is yet to be conducted. Moreover, whether de-differentiation of mature adipocytes from classical subcutaneous and visceral depots occurs under physiological conditions remains unknown.

In our latest paper, we used in vitro”ceiling culture”,single cell/nucleus RNA sequencing, epigenetic analysis and genetic lineage tracing to address these questions.

The paper has been published in Molecular Metabolism