Monther Abu-Remaileh (Stanford University, Stanford, USA) and his group showed that CLN3 is required for the clearance of glycerophosphodiesters (GPDs) from lysosomes. The CLN3 gene was first described in 1995. For the first time in the history of CLN3 research, the paper with first author Nouf N. Laqtom describes a fundamental defect inside the lysosomes of CLN3-deficient cells where a group of GPD metabolites accumulate and fail to exit the lysosome when CLN3 is defect.
GPDs are the final breakdown products of the intra-lysosomal catabolism of an important class of membrane proteins (glycerophospholipids). GPDs need to exit the lysosome before they can be reutilized and serve as building blocks for the synthesis and renewal of membrane lipids. Monther`s team also showed that the failure of GPDs to exit lysosomes results downstream in a significant reduction of lysosomal GPDs being reutilized as components of membrane lipids. This finding seems to support the working hypothesis that nutrient deprivation might be one of the disease components in CLN3.
GPDs also appear in biofluids, including the cerebrospinal fluid (CSF). The presence of glycerophosphoinositol (GPI) was demonstrated in the CSF of CLN3 patients by Monther's team in collaboration with An Dang Do and Forbes D. Porter at NIH. Furthermore, Jill Weimer`s team at Sanford reported GPDs in CLN3 patient blood, in blood and CSF of their CLN3 minipig model, and in the blood of a CLN3 mouse model. GPDs and in particular GPI in the CSF of CLN3 patients might therefore have potential as a disease biomarker.
Altogether the findings offer new approaches for therapy and early diagnosis, and provide a framework for further groundbreaking studies.
Congratulations to Monther and his group! We are more than happy about the results.
A big thank you goes to Stichting Beat Batten!, Contactpunt NCL, Eagles Krimi-Cup, Hauschildt Stiftung and Joachim Herz Stiftung for the generous funding of this pioneering project.
You will find the paper "CLN3 is required for the clearance of glycerophosphodiesters from lysosomes" here.