Shared pathologies of the lysosomal disorder storages Parkinson’s disease and Neuronal CeroidLipofuscinoses

SCHEME: INTER Mobility

CALL: 2015

DOMAIN: BM - Life Sciences, Biology and Medicine

FIRST NAME: Anna-Lena

LAST NAME: Hillje

INDUSTRY PARTNERSHIP / PPP: No

INDUSTRY / PPP PARTNER:

HOST INSTITUTION: University of Luxembourg

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

START: 2016-07-01

END: 2017-12-30

WEBSITE: https://www.uni.lu

Submitted Abstract

Kufor Rakeb Syndrom (KRS) is a rare, heritable form of Parkinson’s Disease (PD) with juvenile onset andunknown cause. Similar to other variants of PD, the loss of dopamine producing neurons in the substantianigra causes a lack of the neurotransmitter dopamine, which leads to a reduction of the activating functionof basal ganglia on the cortex. Lack of dopamine causes the typical symptoms like rigidity, bradykinesiaand tremor. By the time of diagnosis 50-60% of dopaminergic neurons are degenerated. Recently, a linkbetween the functionality of the gene ATP13A2 and the onset of KRS has been shown. ATP13A2 plays animportant role in lysosome function. Lysosomes are membrane-enclosed organelles that contain a varietyof different enzymes capable of degrading biological polymers. By up-taking and breaking down proteinsand other material that is targeted for degradation, 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 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 humanmaterial is very hard to obtain and only available at the end stage of a disease, in vitro modelling ofneurodegenerative diseases is extremely important to gain further insight into onset and progression of adisease. Furthermore, such in vitro models are valuable tools for drug testing. In the current project we arestudying, how mutations in ATP13A2 cause the onset of the two different neurodegenerative diseases. Wedeveloped disease models that are based on human pluripotent stem cells (hiPSCs) carrying ATP13A2mutations. We were using the new CRISPR/Cas9 technology to introduce the KRS and NCL linkedmutations in ATP13A2 into the genome of the hiPSCs. The modified cells will on the one hand bedifferentiated into neurons, which enables us to study the effect of the mutations in exactly the cell type thatundergoes 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 precedeneurodegeneration.In the iPSC derived disease specific neurons we will study the functionality of lysosomes and correlate thiswith 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 eachother to uncover signalling pathways that might cause the disease. After characterising and understandingthe errant pathways, our modified cells provide an excellent model to develop and test new therapeuticalapproaches.We are convinced that our work contributes to the understanding of the so far not well studied juvenile formof 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 achallenging and promising approach.

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