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Early developmental alteration of neurite outgrowth occurs besides late-appearing neurodegenerative processes in Wolfram syndrome

ABSTRACT: Developmental alteration in brain wiring that would make it more susceptible to later pathological processes has been suggested as a basis for the occurrence of neurodegenerative diseases, but mechanisms have remained elusive. A recent series of magnetic resonance imaging studies have demonstrated that, in Wolfram syndrome, neurodegenerative processes appear during childhood and adolescence on top of a clinically silent global defect in brain development. Here, differentiation of induced pluripotent stem cell lines derived from Wolfram syndrome patients’ cells along the neural lineage has revealed phenotypic and molecular correlates of that global brain defect. A proportion of neural cells displayed aberrant neurite outgrowth associated with alterations in the expression of genes involved in axonal guidance. In contrast, an activation of endoplasmic reticulum stress response genes was absent while it is present in late Wolfram syndrome degenerative processes. These results concur to the broader hypothesis that axon guidance genes may play a role in the susceptibility to neurodegenerative diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156911 | GEO | 2021/09/23

REPOSITORIES: GEO

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Project description:Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders. Wolfram syndrome (WS) mainly caused by WFS1 deficiency is a monogenic genetic disease manifested by severe psychiatric disorders. Due to athe lack of proper human disease models, the underlying mechanism is poorly understood. Particularly, whether and how WFS1 deficiency affects synapse formation remain elusive. By mirroring the complexity of human brain development with cerebral organoids derived from human embryonic stem cells (hESCs) harboring WFS1 loss of function (LOF), we found that WFS1-deficient cerebral organoids not only recapitulated the neuronal loss phenotype in WS patients, but also exhibited significantly impaired synapse formation associated with reduced astrocytes, suggesting a defective structural basis for psychiatric disorders elicited by WFS1 deficiency. To further unravel the complexity of interplay between neurons and astrocytes, each neural cell type was respectively differentiated from hESCs harboring WFS1 LOF. WFS1 deficiency in neurons autonomously delayed neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impaired neurite outgrowth and reduced synapse formation associated with elevated cytosolic calcium. Interestingly, WFS1 deficiency in astrocytes decreased the expression of glutamate transporter EAAT2 and compromised glutamate uptake, causing reduced neurite outgrowth with increased cytosolic calcium when co-cultured with wildtype (WT) neurons, highlighting pathogenic role of WFS1-deficient astrocytes. Importantly, restoring EAAT2 expression in astrocytes by riluzole treatment significantly alleviated reduced neurite outgrowth phenotype in WT neurons co-cultured with WFS1-deficient astrocytes. Altogether, our study provides novel insights into how WFS1 deficiency affects neurite outgrowth and synapse formation, potentially contributing to predisposition of psychiatric disorders, and offers a potential strategy of therapy.

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Early developmental alteration of neurite outgrowth occurs besides late-appearing neurodegenerative processes in Wolfram syndrome

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