Biology subjects

Perlstein, E.

Publications and source records attributed to Perlstein, E..

3 recordsLinked to original sources

bioRxiv2024

Deep learning-driven neuromorphogenesis screenings identify repurposable drugs for mitochondrial disease

Mitochondrial disease encompasses untreatable conditions affecting tissues with high energy demands. A severe manifestation of mitochondrial disease is Leigh syndrome (Leigh), which causes defects in basal ganglia and midbrain regions, psychomotor regression, lactic acidosis, and early death. We previously generated isogenic pairs of Leigh cerebral organoids and uncovered defects in neuromorphogenesis. Here, we leveraged on this disease feature to devise drug discovery pipelines. We developed a deep learning algorithm tailored for cell type-specific drug repurposing to identify drugs capable of promoting neuronal commitment. In parallel, we performed a survival drug screen in yeast and validated the repurposable hits on branching capacity in Leigh neurons. The two approaches independently highlighted azole compounds, Talarozole and Sertaconazole, both of which lowered lactate release and improved neurogenesis and neurite organization in Leigh midbrain organoids. Hence, targeting neuromorphogenesis has led to identify potential new drugs for mitochondrial disease and could prove an effective strategy for further drug discovery.

neuroscience↗

bioRxiv2019

Drug screens of NGLY1 Deficiency worm and fly models reveal catecholamine, NRF2 and anti-inflammatory pathway activation as clinical approaches

N-glycanase 1/NGLY1 Deficiency is an ultra-rare and complex monogenic glycosylation disorder that affects fewer than 40 patients globally. NGLY1 Deficiency has been studied in model organisms such as yeast, worms, flies and mice. Proteasomal and mitochondrial homeostasis gene networks are controlled by the evolutionarily conserved transcriptional regulator Nrf1, whose activity requires deglycosylation by NGLY1. Hypersensitivity to the proteasome inhibitor bortezomib is a common phenotype observed in whole animal and cellular models of NGLY1 Deficiency. Here we describe unbiased phenotypic drug screens to identify FDA approved drugs, generally recognized as safe natural products and novel chemical entities that rescue growth and development of NGLY1-deficient worm and fly larvae treated with a toxic dose of bortezomib. We used image-based larval size and number assays for use in screens of a 2,560-member drug repurposing library and a 20,240-member lead discovery library. A total of 91 validated hit compounds from primary invertebrate screens were tested in a human cell line in a NRF2 activity assay. NRF2 is a transcriptional regulator that regulates cellular redox homeostasis and it can compensate for loss of Nrf1. Plant-based polyphenols comprise the largest class of hit compounds and NRF2 inducers. Catecholamines and catecholamine receptor activators comprise the second largest class of hits. Steroidal and non-steroidal anti-inflammatory drugs comprise the third largest class. Only one compound was active in all assays and species: the atypical antipsychotic and dopamine receptor agonist aripiprazole. Worm and fly models of NGLY1 Deficiency validate therapeutic rationales for activation of NRF2 and anti-inflammatory pathways based on results in mice and human cell models and suggest a novel therapeutic rationale for boosting catecholamine levels and/or signaling in the brain.

pharmacology and toxicology↗

bioRxiv2018

Defects in the neuroendocrine axis cause global development delay in aDrosophila model of NGLY1 Deficiency

N-glycanase 1 (NGLY1) Deficiency is a rare monogenic multi-system disorder first described in 2014. NGLY1 is evolutionarily conserved in model organisms, including the Drosophila melanogaster NGLY1 homolog, Pngl. Here we conducted a natural history study and chemical-modifier screen on a new fly model of NGLY1 Deficiency engineered with a nonsense mutation in Pngl at codon 420, resulting in truncation of the C-terminal carbohydrate-binding PAW domain. Homozygous mutant animals exhibit global development delay, pupal lethality and small body size as adults. We developed a 96-well-plate, image-based, quantitative assay of Drosophila larval size for use in a screen of the 2,650-member Microsource Spectrum compound library of FDA approved drugs, bioactive tool compounds, and natural products. We found that the cholesterol-derived ecdysteroid molting hormone 20-hydroxyecdysone (20E) rescued the global developmental delay in mutant homozygotes. Targeted expression of a human NGLY1 transgene to tissues involved in ecdysteroidogenesis, e.g., prothoracic gland, also rescues global developmental delay in mutant homozygotes. Finally, the proteasome inhibitor bortezomib is a potent enhancer of global developmental delay in our fly model, evidence of a defective proteasome \"bounce-back\" response that is also observed in nematode and cellular models of NGLY1 Deficiency. Together, these results demonstrate the therapeutic relevance of a new fly model of NGLY1 Deficiency for drug discovery, biomarker discovery, pharmacodynamics studies, and gene modifier screens.

genetics↗