Targeting autophagy impairment improves the phenotype of a novel CLN8 zebrafish model

• Published in: Neurobiology of disease Vol. 197; p. 106536
• Main Authors: Marchese, Maria, Bernardi, Sara, Ogi, Asahi, Licitra, Rosario, Silvi, Giada, Mero, Serena, Galatolo, Daniele, Gammaldi, Nicola, Doccini, Stefano, Ratto, Gian Michele, Rapposelli, Simona, Neuhauss, Stephan C.F., Zang, Jingjing, Rocchiccioli, Silvia, Michelucci, Elena, Ceccherini, Elisa, Santorelli, Filippo M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2024; Academic Press; Elsevier
• Subjects: Autophagy; Drug screening; Neuronal ceroid lipofuscinosis 8; Zebrafish; FDA; NMD; IDA; Zebrafish; Drug screening; Autophagy; ER; ROI; AO; Neuronal ceroid lipofuscinosis 8; CES; NCL; TTBS; LFP; RMS; dpf; DEPs; ERG; DIA; WT; CTSD; SCMAS; hpf; CID
• ISSN: 0969-9961; 1095-953X; 1095-953X
• DOI: 10.1016/j.nbd.2024.106536

CLN8 is an endoplasmic reticulum cargo receptor and a regulator of lysosome biogenesis whose loss of function leads to neuronal ceroid lipofuscinosis. CLN8 has been linked to autophagy and lipid metabolism, but much remains to be learned, and there are no therapies acting on the molecular signatures in this disorder. The present study aims to characterize the molecular pathways involved in CLN8 disease and, by pinpointing altered ones, to identify potential therapies. To bridge the gap between cell and mammalian models, we generated a new zebrafish model of CLN8 deficiency, which recapitulates the pathological features of the disease. We observed, for the first time, that CLN8 dysfunction impairs autophagy. Using autophagy modulators, we showed that trehalose and SG2 are able to attenuate the pathological phenotype in mutant larvae, confirming autophagy impairment as a secondary event in disease progression. Overall, our successful modeling of CLN8 defects in zebrafish highlights this novel in vivo model's strong potential as an instrument for exploring the role of CLN8 dysfunction in cellular pathways, with a view to identifying small molecules to treat this rare disease. [Display omitted] •In vivo exploration of CLN8 dysfunction showed an impaired autophagy.•Using autophagy modulators, showed that autophagy impairment is a secondary event in disease progression.•The successful modeling of CLN8 defects in zebrafish highlights its potential in identifying novel disease pathways and drugs.