Adaptive preconditioning in neurological diseases -­ therapeutic insights from proteostatic perturbations

International audienceIn neurological disorders, both acute and chronic neural stress can disrupt cellular proteostasis, resulting in the generation of pathological protein. However in most cases, neurons adapt to these proteostatic perturbations by activating a range of cellular protective and repair responses, thus maintaining cell function. These interconnected adaptive mechanisms comprise a 'proteostasis network' and include the unfolded protein response, the ubiquitin proteasome system and autophagy. Interestingly, several recent studies have shown that these adaptive responses can be stimulated by preconditioning treatments, which confer resistance to a subsequent toxic challenge - the phenomenon known as hormesis. In this review we discuss the impact of adaptive stress responses stimulated in diverse human neuropathologies including Parkinson´s disease, Wolfram syndrome, brain ischemia, and brain cancer. Further, we examine how these responses - and the molecular pathways they recruit - might be exploited for therapeutic gai

Visual phenotyping of Wfs1 mutant mice, models of Wolfram syndrome neuronal and diabetic symptoms

Purpose: Wolfram syndrome is an early onset genetic disease (1/160,000) featuring diabetes mellitus and optic neuropathy, associated to mutation in the WFS1 gene. Mouse model with deleted exon 8 of Wolframin shows pancreatic beta cell atrophy, but its visual performance has not been investigated, prompting us to study its visual function and the histopathology of the retina and optic nerve. Methods: Electroretinogram (ERG, retinal function) and visual evoked potentials (VEPs, visual pathway) were performed in Wfs1-/- and Wfs1+/+ mice at 3, 6 and 9 months of age. Fundi were pictured with Micron III apparatus. Retinal ganglion cell (RGC) proportion was determined from Brn3a immuno-labeling of retinal sections. RGC axonal loss was quantified by electron microscopy in transversal optic nerve sections. Results: ERG showed a sex-dependent alteration in Wfs1 mutant mice at 3 months. Photoreceptor response amplitude (a-wave) was increased by 25.5% by Wfs1 mutation in females, while reduced by 28.2% in males. In contrast, positive scotopic threshold responses (pSTR) at the same age were found increased in mutant group by 20.5%. A preliminary study of 7 months male samples showed a severe loss of RGC somas (-50%) and axons in retina and optic nerve respectively. Finally, 7-8 months knocked-in mice presented a severe ocular hypertension. Conclusions: Electrophysiological phenotyping of Wfs1 deleted mouse exon 8 visual function indicate a significant loss of RGC in mutant mouse at 7 month. Structural analysis of retinal ganglion cell somas and axons are conducted to characterize optic neuropathy in these animals