PATHOGENIC MECHANISMS IN CLN6
CLN6 is a protein that is localized in the membrane of the endoplasmic reticulum (1). Mutations of the CLN6 gene lead to a disease termed neuronal ceroid lipofuscinosis. In this neurogenerative lysosomal storage disorder proteins and lipids, for example, are no longer degraded in the lysosomes of cells and accumulate. The disease onset is mostly in early childhood and leads to a progressive mental and motor decline resulting in premature death (2). Why a mutation in the CLN6 gene leads to a lysosomal dysfunction is not known. As CLN6 is located in the ER, it could possibly act as a chaperone for lysosomal proteins or mediate ER-lysosome contacts and thereby influence lysosomal function. The goal of our project is to identify novel interaction partners of the CLN6 protein in the cell and particularly on lysosomes.
To yield further information about the disease mechanisms and to discover the influence of CLN6 deficiency on the lysosomal proteome composition, we want to quantitatively compare of lysosomes from cells defect in CLN6 with those of control cells. This will be accomplished by magnetic isolation of lysosomes followed by a mass spectrometric analysis (3).
- Heine C, Quitsch A, Storch S, Martin Y, Lonka L, Lehesjoki AE, et al. (2007) Topology and endoplasmic reticulum retention signals of the lysosomal storage disease-related membrane protein CLN6. Mol Membr Biol 24: 74-87
- Kollmann K, Uusi-Rauva K, Scifo E, Tyynela J, Jalanko A, Braulke T. (2013) Cell biology and function of neuronal ceroid lipofuscinosis-related proteins. Biochim Biophys Acta 1832: 1866-81
- Thelen M, Winter D, Braulke T, Gieselmann V. (2017) SILAC-Based Comparative Proteomic Analysis of Lysosomes from Mammalian Cells Using LC-MS/MS. Methods Mol Biol. 1594: 1-18