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The Role of Microglia in

Neuronal Ceroid Lipofuscionosis

Neuronal ceroid lipofuscionosis (NCL) summarizes a group of human childhood neurodegenerative genetic disorders with occurrence between 1:12,500 and 1:100,000 depending on the genetic background of the population. The phenotypic characteristics of NCL patients include dementia, seizures, and visual loss as an early sign of onset of the disease. So far, 14 disease-causing genes and their genetic mutations are described, however their impact in the fundaments of molecular and cellular dynamics are not well-known. Although mouse models have provided important insights into the disease development from a neuro-centric view, they lack first, the immune-relevant perspective and second, a direct correlation to the human pathophysiology. In addition, several of NCL disease phenotypes could not be recapitulated in mice.

In this proposal, we will study the fundaments of NCL from a novel angle, namely focusing on the impact of genetic mutations within the immune-responsive microglia. We have previously shown that microglia in the retina express a set of NCL disease genes exclusively. This is interesting because microglia have been associated with various neurodevelopmental and neurodegenerative diseases. Hence in our study, we will focus on developing human microglia harboring the disease-causing mutations and analyzing their function. For this, we first use genome-editing to induce the most prevalent NCL genetic mutations in human induced pluripotent stem (iPS) cells. We then differentiate the mutation-carrying and healthy control iPS cells into microglia, and compare their intracellular alterations as well as their interaction with the nervous system. The result of this study will provide important insights into the role of microglia in NCL and could offer a new strategy for cell targeted drug approaches.

Project number: T-948

Call details: Hertha Firnberg Programme

Funding: 64 670 Euro/year +

12 000 Euro/year   

Start date: 2017-08-01

List of Firnberg Grant Recipients