Neuronopathic Gaucher disease models reveal defects in cell growth promoted by Hippo pathway activation.
Daria MesselodiSilvia StrocchiSalvatore Nicola BertuccioPascale BadenValentina IndioFederico Manuel GiorgiAlberto TaddiaSalvatore SerravalleSabrina ValenteAlessio di FonzoEmanuele FrattiniRoberto BernardoniAnnalisa PessionDaniela GrifoniMichela DeleidiAnnalisa AstolfiAndrea PessionPublished in: Communications biology (2023)
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.
Keyphrases
- cell death
- cell cycle arrest
- induced apoptosis
- cerebral ischemia
- signaling pathway
- gene expression
- end stage renal disease
- genome wide
- traumatic brain injury
- transcription factor
- ejection fraction
- newly diagnosed
- oxidative stress
- type diabetes
- chronic kidney disease
- prognostic factors
- endoplasmic reticulum stress
- adipose tissue
- brain injury
- spinal cord injury
- patient reported outcomes
- blood brain barrier
- single cell
- drug induced
- soft tissue
- dna methylation
- lps induced