In a new study we provide multiple lines of evidence that the lysosomal integral membrane protein type 2 (LIMP-2/SCARB2) participates in lipid transport from lysosomes by transporting cholesterol (and possibly also other lipid species) through its luminal cavity to the lysosomal membrane.

Our experiments support a fundamental physiological role of LIMP-2 in lipid transport alongside the known NPC1 and NPC2 pathways. Our results may help direct the development of drugs that can enhance lipid recycling out of the lysosome and/or alleviate the negative consequences of lipidoses.

This study is a nice example of a successful collabporative effort with experiments performed in Canada (S. Grinstein), China (D. Neculai) and Europe (E.Ikonen, P. Saftig).

Suggested reading:

Heybrock S, Kanerva K, Meng Y, Ing C, Liang A, Xiong ZJ, Weng X, Ah Kim Y, Collins R, Trimble W, Pomès R, Privé GG, Annaert W, Schwake M, Heeren J, Lüllmann-Rauch R, Grinstein S, Ikonen E, Saftig P, Neculai D. (2019)
Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export.
Nat Commun.10(1):3521.

Cathepsin D is one of the major lysosomal proteases indispensable for the maintenance of cellular proteostasis by turning over substrates of endocytosis, phagocytosis and autophagy. Consequently, CTSD deficiency leads to a strong impairment of the lysosomal-autophagy machinery. In mice and humans CTSD dysfunction underlies the congenital variant (CLN10) of neuronal ceroid lipofuscinosis (NCL).Here we reveal that recombinant human pro-CTSD produced in a mammalian expression system can be efficiently taken up by a variety of cell models, is correctly targeted to lysosomes and processed to the active mature form of the protease. In proof-of-principle experiments we provide evidence that recombinant human CTSD (rhCTSD) can improve the biochemical phenotype of CTSD-deficient hippocampal slice cultures in vitro and retinal cells in vivo. Furthermore, we demonstrate that dosing of rhCTSD in the murine CLN10 model leads to a correction of lysosomal hypertrophy, storage accumulation and impaired autophagic flux in the viscera and central
nervous system (CNS). We establish that direct delivery of the recombinant protease to the CNS is required for improvement of neuropathology and
lifespan extension. Together these data support the continuation of the preclinical studies for the application of rhCTSD in the treatment of NCL.


Suggested Reading:

Marques, A.R.A., Di Spiezio, A., Thießen,T., Schmidt, L., Grötzinger, J., Lüllmann-Rauch, R., Damme, M., Storck, S.E., Pietrzik, C.U., Fogh, J., Bär,J., Mikhaylova, M., Glatzel, M., Bassal, M., Bartsch, U., Saftig, P. (2019)
Enzyme replacement therapy with recombinant pro-CTSD (cathepsin D) corrects defective proteolysis and autophagy in neuronal ceroid lipofuscinosis.
Autophagy, in press