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

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. 6 samples (3 wildtype (WT1, WT2, WT3) and 3 wolfram (WS1, WS2, WS)) for NSCs and 6 samples (3 wildtype (WT1, WT2, WT3) and 3 wolfram (WS1, WS2, WS)) for neurons.