An in vivo drug repurposing screen and transcriptional analyses reveals the serotonin pathway and GSK3 as major therapeutic targets for NGLY1 deficiency

Hope, Kevin A.; Berman, Alexys R.; Peterson, Randall T.; Chow, Clement Y.

doi:10.1371/journal.pgen.1010228

Cited by 11 publications

(13 citation statements)

References 50 publications

(90 reference statements)

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“…More in-depth study in a dopaminergic neuronal model of NGLY1 disease is required to understand the disruption of the dopaminergic system in NGLY1 disorder. Non-etheless, our results are consistent with findings from two drug repurposing screens in worm ( Iyer et al, 2019 ) and fly models of NGLY1 deficiency ( Hope et al, 2022 ), which identified compounds that modulate the dopamine pathway to reverse NGLY1 related phenotype. Additionally, the NGLY1 deficient organoids showed a reduction in GABA neurotransmitter up to day 45.…”

Section: Discussionsupporting

confidence: 86%

“…Despite multiple studies performed in model organisms ( Tambe et al, 2019 ; Han et al, 2020 ; Talsness et al, 2020 ), the pathogenesis of NGLY1 deficiency is still poorly understood. Recent studies focusing on neurological phenotypes of NGLY1 disorder have shown disruptions in ion channels, monoamine pathways and dysregulation in stress responses ( Owings et al, 2018 ; Mueller et al, 2020 ; Hope et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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Generation and characterization of NGLY1 patient-derived midbrain organoids

Abbott

Tambe²,

Pavlinov³

et al. 2023

Front. Cell Dev. Biol.

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NGLY1 deficiency is an ultra-rare, autosomal recessive genetic disease caused by mutations in the NGLY1 gene encoding N-glycanase one that removes N-linked glycan. Patients with pathogenic mutations in NGLY1 have complex clinical symptoms including global developmental delay, motor disorder and liver dysfunction. To better understand the disease pathogenesis and the neurological symptoms of the NGLY1 deficiency we generated and characterized midbrain organoids using patient-derived iPSCs from two patients with distinct disease-causing mutations–one homozygous for p. Q208X, the other compound heterozygous for p. L318P and p. R390P and CRISPR generated NGLY1 knockout iPSCs. We demonstrate that NGLY1 deficient midbrain organoids show altered neuronal development compared to one wild type (WT) organoid. Both neuronal (TUJ1) and astrocytic glial fibrillary acid protein markers were reduced in NGLY1 patient-derived midbrain organoids along with neurotransmitter GABA. Interestingly, staining for dopaminergic neuronal marker, tyrosine hydroxylase, revealed a significant reduction in patient iPSC derived organoids. These results provide a relevant NGLY1 disease model to investigate disease mechanisms and evaluate therapeutics for treatments of NGLY1 deficiency.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Generation and characterization of NGLY1 patient-derived midbrain organoids

Abbott

Tambe²,

Pavlinov³

et al. 2023

Front. Cell Dev. Biol.

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“…Larvae were imaged at 2.5× magnification using a Leica EC3 camera. Larval size was quantified using ImageJ as previously described ( Hope et al 2022 ). All larval measurements were performed with at least 20 larvae per genotype.…”

Section: Methodsmentioning

confidence: 99%

Drosophila models of phosphatidylinositol glycan biosynthesis class A congenital disorder of glycosylation (PIGA-CDG) mirror patient phenotypes

Thorpe,

Owings,

Aziz

et al. 2023

G3: Genes, Genomes, Genetics

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Mutations in the phosphatidylinositol glycan biosynthesis class A (PIGA) gene cause a rare, X-linked recessive congenital disorder of glycosylation (CDG). PIGA-CDG is characterized by seizures, intellectual and developmental delay, and congenital malformations. The PIGA gene encodes an enzyme involved in the first step of GPI anchor biosynthesis. There are over 100 GPI anchored proteins that attach to the cell surface and are involved in cell signaling, immunity, and adhesion. Little is known about the pathophysiology of PIGA-CDG. Here we describe the first Drosophila model of PIGA-CDG and demonstrate that loss of PIG-A function in Drosophila accurately models the human disease. As expected, complete loss of PIG-A function is larval lethal. Heterozygous null animals appear healthy, but when challenged, have a seizure phenotype similar to what is observed in patients. To identify the cell-type specific contributions to disease, we generated neuron- and glia-specific knockdown of PIG-A. Neuron-specific knockdown resulted in reduced lifespan and a number of neurological phenotypes, but no seizure phenotype. Glia-knockdown also reduced lifespan and, notably, resulted in a very strong seizure phenotype. RNAseq analyses demonstrated that there are fundamentally different molecular processes that are disrupted when PIG-A function is eliminated in different cell types. In particular, loss of PIG-A in neurons resulted in upregulation of glycolysis, but loss of PIG-A in glia resulted in upregulation of protein translation machinery. Here we demonstrate that Drosophila is a good model of PIGA-CDG and provide new data resources for future study of PIGA-CDG and other GPI anchor disorders.

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“…Importantly, the broad scope of ES/GS can, in rare instances, dramatically expedite diagnosis-specific interventions for patients who present with a nonspecific phenotype ( 73 ). Further, the rapid identification of specific variants fostered innovative interventions such as the repurposing of existing medications to target the biochemical pathway impacted by pathogenic variants ( 74 , 75 ), and the development of antisense oligonucleotides targeted to specific pathogenic variants that inhibit aberrant protein production ( 76 ). With better refinement of NGS technologies, these tangible benefits to patients are likely to increase.…”

Section: Impact Of Exome and Genome Sequencing On Undiagnosed Syndromesmentioning

confidence: 99%

Exome/Genome Sequencing in Undiagnosed Syndromes

et al. 2023

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Exome sequencing (ES) and genome sequencing (GS) have radically transformed the diagnostic approach to undiagnosed rare/ultrarare Mendelian diseases. Next-generation sequencing (NGS), the technology integral for ES, GS, and most large (100+) gene panels, has enabled previously unimaginable diagnoses, changes in medical management, new treatments, and accurate reproductive risk assessments for patients, as well as new disease gene discoveries. Yet, challenges remain, as most individuals remain undiagnosed with current NGS. Improved NGS technology has resulted in long-read sequencing, which may resolve diagnoses in some patients who do not obtain a diagnosis with current short-read ES and GS, but its effectiveness is unclear, and it is expensive. Other challenges that persist include the resolution of variants of uncertain significance, the urgent need for patients with ultrarare disorders to have access to therapeutics, the need for equity in patient access to NGS-based testing, and the study of ethical concerns. However, the outlook for undiagnosed disease resolution is bright, due to continual advancements in the field.

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An in vivo drug repurposing screen and transcriptional analyses reveals the serotonin pathway and GSK3 as major therapeutic targets for NGLY1 deficiency

Cited by 11 publications

References 50 publications

Generation and characterization of NGLY1 patient-derived midbrain organoids

Generation and characterization of NGLY1 patient-derived midbrain organoids

Drosophila models of phosphatidylinositol glycan biosynthesis class A congenital disorder of glycosylation (PIGA-CDG) mirror patient phenotypes

Exome/Genome Sequencing in Undiagnosed Syndromes

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