A Multilevel Screening Pipeline in Zebrafish Identifies Therapeutic Drugs for GAN

Giant axonal neuropathy (GAN) is a fatal neurodegenerative disorder for which there is currently no treatment

Lescouzères, L.; Hassen‐Khodja, C.; Baudot, A.; Bordignon, B.; Bomont, P.
EMBO Molecular Medicine e16267 (2023)

Affecting the nervous system, GAN starts in infancy with motor deficits that rapidly evolve toward total loss of ambulation. Using the gan zebrafish model that reproduces the loss of motility as seen in patients, we conducted the first pharmacological screening for the GAN pathology. Here, we established a multilevel pipeline to identify small molecules restoring both the […]

Leveraging Genetic Diversity to Identify Small Molecules That Reverse Mouse Skeletal Muscle Insulin Resistance

Systems genetics has begun to tackle the complexity of insulin resistance by capitalising on computational advances to study high-diversity populations

Masson, S. W. C.; Madsen, S.; Cooke, K. C.; Potter, M.; Vegas, A. D.; Carroll, L.; Thillainadesan, S.; Cutler, H. B.; Walder, K. R.; Cooney, G. J.; Morahan, G.; Stöckli, J.; James, D. E.
Elife RP86961 (2023)

‘Diversity Outbred in Australia (DOz)’ is a population of genetically unique mice with profound metabolic heterogeneity. We leveraged this variance to explore skeletal muscle’s contribution to whole-body insulin action through metabolic phenotyping and skeletal muscle proteomics of 215 DOz mice. Linear modelling identified 553 proteins that associated with whole-body insulin sensitivity (Matsuda Index) including regulators […]

Cardiac Glycosides Restore Autophagy Flux in an iPSC-Derived Neuronal Model of WDR45 Deficiency

Beta-Propeller Protein-Associated Neurodegeneration (BPAN) is one of the commonest forms of Neurodegeneration with Brain Iron Accumulation, caused by mutations in the gene encoding the autophagy-related protein, WDR45.

Papandreou, A.; Singh, N.; Gianfrancesco, L.; Budinger, D.; Barwick, K.; Agrotis, A.; Luft, C.; Shao, Y.; Lenaerts, A.-S.; Gregory, A.; Jeong, S. Y.; Hogarth, P.; Hayflick, S.; Barral, S.; Kriston-Vizi, J.; Gissen, P.; Kurian, M. A.; Ketteler, R.
bioRxiv 556416 (2023)

The mechanisms linking autophagy, iron overload and neurodegeneration in BPAN are poorly understood and, as a result, there are currently no disease-modifying treatments for this progressive disorder. We have developed a patient-derived, induced pluripotent stem cell (iPSC)-based midbrain dopaminergic neuronal cell model of BPAN (3 patient, 2 age-matched controls and 2 isogenic control lines) which […]

Syrosingopine Enhances 20S Proteasome Activity and Degradation of α-Synuclein

Cellular proteins are degraded by the 26S proteasome in the ubiquitin-proteasome system in an ATP-dependent manner, whereas intrinsically disordered proteins (IDPs) are degraded by the 20S proteasome independent of ATP and ubiquitin.

Sadahiro, Y.; Nishimura, S.; Hitora, Y.; Tsukamoto, S.
J Nat Prod (2023)

The accumulation and aggregation of IDPs are considered to be the etiology of neurodegenerative diseases. Notably, the 20S proteasome has a cylindrical structure, and its gate on the α-ring is closed in the inactive form. The compounds that open the gate promote the degradation of IDPs and prevent their accumulation, and therefore, such compounds may […]

Screening for New Inhibitors of the Human Mitochondrial Pyruvate Carrier and Their Effects on Hepatic Glucose Production and Diabetes

The mitochondrial pyruvate carrier (MPC) is a protein complex composed of two subunits, MPC1 and MPC2

Herzig, S.; Li, L.; Jiménez-Sánchez, C.; Martinou, J.-C.; Maechler, P.
Biochim Biophys Acta Gen Subj 130492 (2023)

This carrier is at the interface between glycolysis and mitochondrial metabolism and plays an essential role in hepatic glucose production.

Simple Droplet Microfluidics Platform for Drug Screening on Cancer Spheroids

3D in vitro biological systems are progressively replacing 2D systems to increase the physiological relevance of cellular studies

Parent, C.; Melayil, K. R.; Zhou, Y.; Aubert, V.; Surdez, D.; Delattre, O.; Wilhelm, C.; Viovy, J.-L.
Lab Chip 5139–5150 (2023)

Microfluidics-based approaches can be powerful tools towards such biomimetic systems, but often require high-end complicated and expensive processes and equipment for microfabrication. Herein, a drug screening platform is proposed, minimizing technicality and manufacturing steps. It provides an alternate way of spheroid generation in droplets in tubes. Droplet microfluidics then elicit multiple droplets merging events at […]

Accumulation of Endogenous Free Radicals Is Required to Induce Titan-like Cell Formation in Cryptococcus Neoformans

Cryptococcus neoformans is an encapsulated yeast able to cause disease (mainly meningoencephalitis) among immunosuppressed patients, mostly HIV+

García-Barbazán, I.; Torres-Cano, A.; García-Rodas, R.; Sachse, M.; Luque, D.; Megías, D.; Zaragoza, O.
mBio e02549-23 (2023)

This yeast can form the so-called titan cells in vivo, which are cells of an abnormally larger size due to an increase in both the capsule and the cell body size (total size reaching between 50–70 μm). This phenomenon can be partially reproduced in vitro to obtain cells of an intermediate size (25–30 μm), which […]

GSK3 Inhibition Reduces ECM Production and Prevents Age-Related Macular Degeneration-like Pathology

Malattia Leventinese/Doyne Honeycomb Retinal Dystrophy (ML/DHRD) is an age-related macular degeneration (AMD)-like retinal dystrophy caused by an autosomal dominant R345W mutation in the secreted glycoprotein, fibulin-3 (F3)

DiCesare, S. M.; Ortega, A. J.; Collier, G. E.; Daniel, S.; Thompson, K. N.; McCoy, M. K.; Posner, B. A.; Hulleman, J. D.
bioRxiv December 15 p 2023.12.14.571757 (2023)

To identify new small molecules that reduce F3 production from retinal pigmented epithelium (RPE) cells, we knocked-in a luminescent peptide tag (HiBiT) into the endogenous F3 locus which enabled simple, sensitive, and high throughput detection of the protein. The GSK3 inhibitor, CHIR99021 (CHIR), significantly reduced F3 burden (expression, secretion, and intracellular levels) in immortalized RPE […]

Metixene Is an Incomplete Autophagy Inducer in Preclinical Models of Metastatic Cancer and Brain Metastases

A paucity of chemotherapeutic options for metastatic brain cancer limits patient survival and portends poor clinical outcomes.

Fares, J.; Petrosyan, E.; Kanojia, D.; Dmello, C.; Cordero, A.; Duffy, J. T.; Yeeravalli, R.; Sahani, M. H.; Zhang, P.; Rashidi, A.; Arrieta, V. A.; Ulasov, I.; Ahmed, A. U.; Miska, J.; Balyasnikova, I. V.; James, C. D.; Sonabend, A. M.; Heimberger, A. B.; Lesniak, M. S
J Clin Invest e161142 (2023)

Using a CNS small-molecule inhibitor library of 320 agents known to be blood-brain barrier permeable and approved by the FDA, we interrogated breast cancer brain metastasis vulnerabilities to identify an effective agent. Metixene, an antiparkinsonian drug, was identified as a top therapeutic agent that was capable of decreasing cellular viability and inducing cell death across […]

Identification of small molecule inhibitors against MMP-14 via High-Throughput screening

Matrix metalloproteinases (MMPs) are involved in various cellular events in physiology and pathophysiology through endopeptidases activity.

Hyun Lee, Isoo Youn, Robel Demissie, Tasneem M Vaid, Chun-Tao Che, Dimitri T Azar, Kyu-Yeon Han
Bioorg Med Chem Volume 85, 1 May 2023, 117289 (2023)

The expression levels and activities of most MMPs remain minimal in the normal conditions, whereas some MMPs are significantly activated in pathological conditions such as cancer and neovascularization. Hence, MMPs are considered as both diagnostic markers and potential targets for therapeutic agents. Twenty-three known human MMPs share a similar active site structure with a zinc-binding […]