Age-related macular degeneration (AMD) is often characterized by the accumulation of cellular and extracellular debris between the outermost layer of the retina—the retinal pigment epithelium (RPE)—and the underlying Bruch’s membrane. Specific sub-RPE deposits known as basal laminar deposits (BLamD) are a common histopathologic finding in early AMD, but it’s still unclear how they are formed. With Shoji Notomi and coworkers the role of lysosome-associated membrane protein-2 (LAMP2), which mediates autophagosome and phagosome maturation, in AMD was analysed. It was found that LAMP2 was primarily expressed in RPE cells and its expression decreased with age in mice as well as in human AMD. Deleting LAMP2 in mice resulted in histopathological changes similar to those seen in AMD, including an increased accumulation of autofluorescent granules and BLamD and a thickening of the Bruch’s membrane. The presence of several key proteins and lipids adjacent to BLamD in LAMP2-deficient mice also resembled features of human AMD. BLamD accumulation in LAMP2-deficient mice was eventually followed by loss of RPE and photoreceptors. In addition, eyes from AMD patients showed reduced LAMP2 expression and disrupted lysosomal structure relative to normal eyes. LAMP2 plays an important role in RPE function, and LAMP2 deficiency may contribute to BLamD formation and AMD pathology.

see:

Notomi, S., Ishihara, K., Efstathiou,N.E., Jong-Jer, L., Hisatomi, T., Tachibana, T., Konstantinou, E., Ueta, T., Murakami, Y., Maidana, D.E., Ikeda,Y., Kume, S., Terasaki, H., Sonoda, S., Blanz, J., Young, L., Sakamoto, T., Sonoda,K.H., Saftig, P., Ishibashi, T., Miller, J.W., Kroemer, G., Vavvas, D.G. (2019) Genetic LAMP2 deficiency accelerates the age-associated formation of basal laminar deposits in the retina. Proc. Natl. Acad. Sci., in press

https://www.pnas.org/content/early/2019/11/06/1906643116

In a new study from our lab with David Massa, Markus Damme and coworkers provide a detailed biochemical characterization of MFSD1. Endogenous MFSD1 is localized in lysosomes. It contains 12 transmembrane domains and it is ubiquitously expressed in murine tissues. It harbors a dileucine-based sorting motif in its cytosolic N-terminus which is required for its transport to lysosomes. In order to decipher the physiological function of MFSD1, we generated and analyzed Mfsd1 knockout (KO) mice. MFSD1-deficient mice develop a severe liver disease characterized by extravasation of erythrocytes, sinusoidal damage,loss of liver sinusoidal endothelial cells (LSECs) and finally signs of fibrosis. By means of differential proteomics of isolated liver lysosomes from wildtype and Mfsd1 KO mice, GLMP was identified as an essential accessory protein for MFSD1. GLMP is a highly glycosylated lysosomal protein of so far unknown function. Deficiency of Mfsd1 leads to drastically reduced levels of GLMP and vice versa. MFSD1 and GLMP physically
interact and Glmp-deficient mice resemble a phenocopy of Mfsd1 KO mice suggesting the MFSD1/
GLMP complex to be a stable and functional relevant lysosomal transporter complex.

Characterizing MFSD1 is important to understand how the lysosomal membrane and transporters work. Moreover, these findings may shed light on how defects in lysosomal transporters contribute to metabolic disease.

Massa Lopez, D., Thelen, M., Stahl, F., Thiel, C., Linhorst, A., Sylvester, M., Hermanns-Borgmeyer, I., ´Lüllmann-Rauch, R., Eskild, W., Saftig, P., Damme, M. (2019) The lysosomal transporter MFSD1 is essential for liver homeostasis and critically depends on its accessory subunit GLMP.
ELife, in press

https://elifesciences.org/articles/50025

The European Commission has announced the winners of the first Horizon Impact Award, a prize dedicated to EU-funded projects that have created societal impact across Europe and beyond. The winning projects have come up with a new drug for a rare disease, helped prevent child abuse, increased security of browsing the web and protected coastal areas against the effects of climate change.

Jean-Eric Paquet, Director-General for Research and Innovation of the Commission, announced the winners at the European Research and Innovation Days in Brussels. An independent jury selected the winning projects.

MANNO-CURE (Kiel Germany) has produced the first long-term drug therapy to treat a rare disease called Alpha-Mannosidosis.

Press release:

https://www.uni-kiel.de/de/universitaet/detailansicht/news/289-horizon-impact-award/

Youtube video:

https://www.youtube.com/watch?v=j1BwFyTowo8