Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation

Abstract

Gaucher Disease (GD), the most common lysosomal disorder, arises from mutations in the GBA1 gene and is characterized by a wide spectrum of phenotypes, ranging from mild hematological and visceral involvement to severe neurological disease. Neuronopathic patients display dramatic neuronal loss and increased neuroinflammation, whose molecular basis are still unclear. Using a combination of Drosophila dGBA1b loss-of-function models and GD patient-derived iPSCs differentiated towards neuronal precursors and mature neurons we showed that different GD- tissues and neuronal cells display an impairment of growth mechanisms with an increased cell death and reduced proliferation. These phenotypes are coupled with the downregulation of several Hippo transcriptional targets, mainly involved in cells and tissue growth, and YAP exclusion from nuclei. Interestingly, Hippo knock-down in the GBA-KO flies rescues the proliferative defect, suggesting that targeting the Hippo pathway can be a promising therapeutic approach to neuronopathic GD.

Genome-wide expression analysis in a Fabry disease human podocyte cell line

“…Moreover, the hippo signaling is interconnected with the Wnt signaling pathway and regulates both innate and adaptive immunity [ 86 ]. A recent study reported that a hyper-activation of hippo pathway alters the growth/death balance and may underlie the neuronal loss in neuronopathic Gaucher disease [ 87 ], which suggested the association between hippo pathway and neurological pain in FD [ 88 ]. In addition, other major partners in Hippo signaling are under-expressed in Fabry podocytes, such as LATS1 and YAP1 .…”

An increase in ER stress and unfolded protein response in iPSCs-derived neuronal cells from neuronopathic Gaucher disease patients

“…Patients carrying L444P mutation exhibit a heterogenous phenotype 2 , including astrogliosis and neuronal loss 7 , 8 . However, it is still unclear what the underlying mechanism of the pathological features observed in the brains of GD patients is, as well as why there is heterogeneity among GD types 5 , 9 . A deeper understanding of the pathophysiology of GD will be invaluable in determining the factors contributing to the variability of its symptoms.…”