Shared pathologies of the lysosomal disorder storages Parkinsons disease and Neuronal Ceroid Lipofuscinoses


CALL: 2015

DOMAIN: BM - Life Sciences, Biology and Medicine





HOST INSTITUTION: University of Luxembourg

KEYWORDS: Parkinsons Disease, Kufor Rakeb Syndrom, Neuronal Ceroid Lipofuscinoses, ATP13A2, Lysosomes, human iPSC, disease modelling

START: 2015-07-01

END: 2016-06-30


Submitted Abstract

Kufor Rakeb Syndrom (KRS) is a rare, heritable form of Parkinson’s Disease (PD) with juvenile onset and unknown cause. Similar to other variants of PD, the loss of dopamine producing neurons in the substantia nigra causes a lack of the neurotransmitter dopamine, which leads to a reduction of the activating function of basal ganglia on the cortex. Lack of dopamine causes the typical symptoms like rigidity, bradykinesia and tremor. By the time of diagnosis 50-60% of dopaminergic neurons are degenerated. Recently, a link between the functionality of the gene ATP13A2 and the onset of KRS has been shown. ATP13A2 plays an important role in lysosome function. Lysosomes are membrane-enclosed organelles that contain a variety of different enzymes capable of degrading biological polymers. By up-taking and breaking down proteins and other material that is not needed anymore, they function as the digestive system of the cell. ATP13A2 localizes in the lysosomal membranes, where it functions as a transport ATPase and critically regulates lysosomal function. Mutations in the ATP13A2 gene lead to a protein that cannot properly localize to the lysosomes. Consequently, the digestive function of the lysosomes is impaired and “cellular waste” accumulates, which might cause cell death. Interestingly, it has been shown that mutations in ATP13A2 do not only cause KRS, but at the same time lead to a juvenile variant of Neuronal Ceroid Lipofuscinoses (NCL). Neuronal Ceroid Lipofuscinoses are neurodegenerative diseases with infantile onset, which are just as KRS classified to the lysosomal storage disorders. Since current mouse models for PD and NCL do not fully resemble the human phenotype and human material is very hard to obtain and only available at the end stage of a disease, in vitro modelling of neurodegenerative diseases is extremely important to gain further insight into onset and progression of a disease. Furthermore, such in vitro models are a valuable tool for drug testing. In the current project we are studying, how mutations in ATP13A2 cause the onset of the two different neurodegenerative diseases. We developed a disease model that is based on human pluripotent stem cells (hiPSCs) carrying ATP13A2 mutations. We were using the new CRISPR/Cas9 technology to introduce the KRS and NCL linked mutations in ATP13A2 into the genome of the hiPSCs. The modified cells will on the one hand be differentiated into neurons, which enables us to study the effect of the mutations in exactly the cell type that undergoes cell death in the brains of KRS and NCL patients. On the other hand, glial cells will be derived, whose activation contributes to inflammatory responses and has been shown to precede neurodegeneration. In the iPSC derived disease specific neurons we will study the functionality of lysosomes and correlate this with protein aggregate formation and cellular phenotypes (e.g. neurite length and cell death). Additionally, gene expression, protein synthesis (proteomics) and metabolomics data are analysed and linked with each other to uncover signalling pathways that might cause the disease. After characterising and understanding the errant pathways, our modified cells provide an excellent model to develop and test new therapeutical approaches. We are convinced that our work contributes to the understanding of the so far not well studied juvenile form of PD as well as NCL and that our model fosters the development of potential therapeutical approaches. Especially the opportunity to study two different diseases by analysing one gene, ATP13A2, makes this a challenging and promising approach.

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