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PD Dr. Markus Damme

Markus Damme
Markus Damme
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Lysosomal Diseases and Characterization of New Lysosomal (Mem­brane) Proteins
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Research
Characterization of new lysosomal membrane proteins of unknown function

Lysosomes are membrane-bound organelles in eukaryotic cells in which (mostly soluble) acidic hydrolases mediate the catabolic degradation of macromolecules like proteins, lipids or oligosaccharides to lower molecular weight metabolites like amino acids, monosaccharides or fatty acids. These metabolites become eventually exported from the lysosomal lumen to the cytosol by specific membranous exporter proteins, where they can be reused for a new round of synthesis. The lysosomal membrane is furthermore protected by highly glycosylated integral membrane proteins from self-digestion by the formation of a glycocalyx.

Although a couple of lysosomal exporters like Sialin, Cystinosin or the Cobalamin exporter where identified and thoroughly characterized in the last years (mostly due to diseases characterized by a deficiency of such exporter proteins and resulting lysosomal storage of the cargo in the lysosomal lumen), a great majority of such proteins was described so far only by means of biochemistry, without identifying the corresponding genes.

Several recent proteomics studies have addressed the identification of new lysosomal membrane proteins including such putative polytopic exporter proteins and integral membrane proteins with unlikely transporter function with only one or two transmembrane domains. Goal of our research is to elucidate the function of such lysosomal membrane proteins of so far unknown function, particularly those whose dysfunction leads to devastating diseases like lysosomal storage diseases or neurodegeneration. We are currently working on several new lysosomal membrane proteins including the putative transporters Mfsd1 and Mfsd8 and the single transmembrane domain containing proteins Ncu-g1 and Tmem106B. Mouse models with loss-of-function are analysed in order to identify putative substrates or to reveal impaired pathological pathways. We are seeking for interaction partners to elucidate the function of the non-transporter proteins.

 
Pathology and therapy of lysosomal storage diseases

The deficiency of lysosomal acid hydrolases leads to the accumulation of undegraded substrates of the corresponding enzyme within the lysosomal lumen. Lysosomal storage results in impaired cellular function and often ultimatively in cell death. Postmitotic cells like neurons are particularly prone to pathological alterations. Therapeutic options are limited, particularly for the brain which is protected by the blood brain barrier, which makes it difficult to treat the brain. One option to treat LSDs is the substitution of the missing hydrolase by injection of recombinantly expressed enzymes into the blood stream. Receptor mediated endocytosis ensures the transport to the lysosome, where the recombinant enzyme can replace the missing hydrolase.

We are currently analysing mouse models for lysosomal storage disorders, both established models (a model fora-Mannosidosis, deficiency of lysosomal a-Mannosidase) and models with new lysosomal storage disorders (Arylsulfatase G deficiency, Mucopolysaccharidosis IIIE; Lysosomal acid phosphatase deficiency), regarding neuropathological alterations and therapeutic options with particular focus on the therapy of the brain.