AI Article Synopsis

  • CLN8 is a receptor involved in cellular processes, and its dysfunction leads to a neurodegenerative disorder known as neuronal ceroid lipofuscinosis, with no current therapies targeting the disease.
  • This study focuses on understanding the molecular pathways affected by CLN8 loss and aims to find potential treatments by using a new zebrafish model that mimics the disease's characteristics.
  • Researchers discovered that CLN8 dysfunction disrupts autophagy and found that compounds like trehalose and SG2 can help alleviate disease symptoms in zebrafish, suggesting new avenues for treatment.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11163972PMC
http://dx.doi.org/10.1016/j.nbd.2024.106536DOI Listing

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