Another groundbreaking discovery by Monther Abu-Remaileh and his team! Last year, the research team of Monther Abu-Remaileh at Stanford University, USA, published a paper in Nature showing for the first time that the CLN3 protein is responsible for the lysosomal clearance of glycerophosphodiesters, GPDs. This groundbreaking finding provides novel insights of the fundamental metabolic changes in juvenile NCL (CLN3) and points at specific potential toxic mechanisms that could play a decisive role in this disease such as detrimental effects caused by GPD accumulation and/or their lysolipid precursors, depletion of building blocks that serve in the renewal of lipid pools, and the depletion of an endo-lysosome-specific lipid (BMP) that serves as an critical co-factor for a host of lysosomal enzymes involved in the degradation of lipids including sphingolipids and glycosphingolipids.

Now came the discovery that CLN5 encodes the long sought-after enigmatic lysosomal enzyme Bis(monoacylglycero)phosphat (BMP) synthase that is responsible for the synthesis of the endo-lysosome-specific lipid BMP. This unique lipid marks the surface of intra-lysosomal vesicles and is a key co-factor required by a host of catabolic lysosomal enzymes to gain access to their lipid substrates. BMP levels are very low and/or dysregulated in several rare (e.g. CLN3, CLN5, CLN11) as well as more common neurodegenerative diseases including GRN-FTD (progranulin haploid insufficiency) and LRRK2-PD. Furthermore, a missense mutation in CLN5 has also been linked to Alzheimer`s disease. BMP synthesis is therefore a therapeutic target of broad interest in neurodegeneration. In other disease areas such as cancer BMPS inhibition seems favorable.

The paper describing the new role of CLN5 was published in September 2023 in Science, with the doctoral student Uche Medoh as first author.

Our warmest congratulations to Uche, Monther and the whole team! We are once again very much impressed by the team`s work and breakthroughs in the NCL field and are happy, together with Beat Batten NL, and others to support Monther's team in advancing NCL research in the hope of finding novel and groundbraking therapeutic entry points.