Neurodegeneration (Luxembourg Center for Systems Biomedicine)

Our aim is to understand the pathological causes and processes of Parkinson’s disease (PD) with the help of mouse models. One of the advantages of mouse models is the possibility to study neurological disease in a mammalian brain that has the basic architecture and cellular composition at least partially similar to those found in the human brain.
In a first approach, PD-like disease is induced in experimental mouse models by either genetic engineering (transgenic, knockout, knockin for familial PD genes), or toxin administration (neurotoxin such as 6-Hydrxydopamine, or alpha-synuclein fibrils). Disease induction is followed up by longitudinal characterisation of pathological changes by behavioral, neuropathological, biochemical, and systems biological measurements.
Using these methods, two novel observations have been made:
(1) The earliest pathological change detected in all models is a distinctive shift in the gene expression signature of midbrain dopaminergic neurons, notably in regulatory transcription factors unique to these neurons. This change is detected months before any visible neurodegeneration is observed. Investigations are underway to determine what causes this gene signature change, and whether it can also be found in the peripheral nervous system (PNS) and could be a biomarker candidate for early PD detection.
(2) In a PD induced model that incorporates prion-like spreading of alpha-synuclein pathology, an exceptionally strong alpha-synuclein aggregation independent microgliosis was found. Current investigations are aimed at determining what causes this microgliosis and if it is a driver of neurodegeneration. 
In as second approach, a mouse genetic reference population, the Collaborative Cross (CC), is used to identify novel genetic regulators of dopaminergic neuron integrity. The demise of these neurons is responsible of the PD-typical decline in motor function. A number of mutations associated with familial PD or sporadic PD risk have been identified, yet few are known that modulate specifically PD-linked decline in motor function. The Neurodegeneration project uses the CC mouse genetic reference population, composed of mouse strains that differ in their dopaminergic function and architecture, to identify novel genetic modulators of these neurons. Neuropathology, neurochemistry, molecular genetics, cell biology, and bioinformatics approaches are used to pursue these goals. Toward the end of this project, it is projected to link the findings, by working with human geneticists, to new gene candidates that govern dopaminergic neuron function in humans.

Neurooncology (Luxembourg Institute of Health)

Glioma cells display a high degree of genetic and epigenetic alterations that frequently lead to altered metabolism. A second important feature of glioma cells is their diffuse infiltration into residual CNS tissue. Our hypothesis is that certain metabolic reprogramming in tumor cells impacts their invasive properties. We therefore aim at deciphering the metabolic signature of diffusely infiltrating cells, compared to the tumor core and normal brain tissue by utilizing non-targeted metabolic analysis of different tumor- and brain regions of the established PDX models. Additionally, we aim at integrating metabolomics with proteomic- and epigenetic data for a better understanding how tumor cell migration and metabolism are interconnected in Glioblastoma multiforme (GBM). The outcome of this project will be the identification of novel metabolic targets to attenuate or possibly prevent the diffuse infiltration of GBM cells.