Early trigeminal and sensory impairment and lysosomal dysfunction in accurate models of Wolfram syndrome

Abstract

Wolfram syndrome (WS) is a rare condition caused by homozygous or compound heterozygous mutations in the WFS1 gene primarily. It is diagnosed on the basis of early-onset diabetes mellitus and optic nerve atrophy. Patients complain of trigeminal-like migraines and show deficits in vibration sensation, but the underlying cause is unknown. Using accurate cell models and two separate, accurate rodent models of WS that show excellent face and construct validity, here we have examined trigeminus, sensation and sensory neuronal function in WS. Analysis of ex vivo and in vivo MRI sequences revealed profound trigeminal atrophy in each rodent model, a novel finding in WS. Optic nerve atrophy is a diagnostic sign in WS, and trigeminal atrophy occurred at the time of earliest loss of optic nerve volume. We also observed deficits in mechanical sensation in our mouse WS model, and pathological analysis revealed extensive inflammation in trigeminal sensory nucleus, both of which are novel findings in WS. Sensory neurons (dorsal root ganglia) showed impaired calcium handling upon depolarisation and reduced mitochondrial membrane potential. Finally, lysosomes were smaller, soma lysosome content was decreased and importantly, lysosome acidity was impaired in sensory neurons, all of which are novel findings in WS. We validated these findings using two separate publicly available datasets, both from WS patient fibroblast-derived neural stem cells. We observed a highly significant functional enrichment of GO cellular component lysosome-related terms among the differentially expressed proteins and genes, with the majority of lysosome-related proteins being downregulated. These data reveal extensive impairments in the trigeminal pathway and nociceptive neurons in WS that may contribute to trigeminal and sensory symptoms observed in patients. Moreover, we note that mutations in WFS1 are relatively common and, given the importance of WFS1 for sensory function, our data may also shed light on sensory impairments in general.

Keywords: Dorsal root ganglia; Inflammation; Lysosome; Magnetic resonance imaging; Mitochondria; Sensory behaviour; Trigeminus.