Research Group Translational Neuroscience

Our research

“Our group carries out fundamental research, clinical research, and integrative care concepts. The fundamental research focus is the elucidation of molecular signalling pathways leading to neurodegeneration in Parkinson’s disease (PD). Using comprehensive genetic analyses in a large sample of Parkinson patients via whole genome sequencing and genome-wide association studies, we have identified novel mutations in genes that are responsible for familial PD and deciphered genetic variants in candidate genes that are associated with sporadic PD.

The clinical research focus is part of the National Centre for Excellence in Research on Parkinson’s Disease (NCER-PD), an initiative of the Luxembourg National Research Fund (FNR). Patients and healthy subjects from Luxembourg and the Greater Region are recruited for a cohort and can directly contribute to PD research by donating biological samples (e.g., DNA, skin). Together with the Centre Hospitalier de Luxembourg (CHL), the Luxembourg Institute of Health (LIH) with the Integrated Biobank of Luxembourg (IBBL), we perform clinical characterisation and biosampling of PD patients.

The Translational Neuroscience Group was established under the auspices of FNR’s PEARL Programme.”

Our Research projects

The Translational Neuroscience group combines fundamental and clinical research and Integrated care concepts:

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    Recent studies found a loss of function of Parkinson’s Disease (PD)-associated proteins PINK1, Parkin and DJ-1, causing impairment of mitochondrial quality control and subsequent loss of neurons. Mitochondrial quality control requires a well-regulated interplay of the mitochondrial Rho GTPase Miro1 with the PINK1/Parkin pathway. The aim of this project is to characterize the influence of Miro1 in pathways relevant to PD, such as mitochondrial energy metabolism, calcium homeostasis, degradation and transport. For this project, we have unique access to novel PD-associated mutations in the RHOT1 gene, encoding Miro1 protein, in order to investigate the consequence of such mutations on mitochondrial and neuronal homeostasis. First results from patient-derived fibroblasts show that mutations of RHOT1 lead to impaired cellular calcium homeostasis and increased mitochondrial turnover, making cells more prone to stress. Currently, we investigate the consequence of the observed mitochondrial phenotypes for neuronal function, using transgenic mice and iPSC-derived neurons.

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    Mutations in more than 20 loci have been identified as being causative for genetic forms of PD. Amongst them mutations in LRRK2 represent the most-common cause of autosomal dominant PD and mutations in parkin are the most-common mutations found in recessive inheritance familial PD. Nevertheless, a heterogeneity in the penetrance of the pathology, the phenotype or the age of onset of patients carrying these mutations leads to the search of associated factors that could influence the development of the disease. Mutations in the GBA gene, encoding the beta-glucocerebrosidase, are an important and common risk factor for both familial and sporadic PD. Carriers of one mutated allele of GBA have a 5-fold increased risk to develop PD and are more likely to progress to dementia, develop axial symptoms and have a slightly earlier age of onset compared to non-carrier PD patients. Underlying these pathological changes, modifications of metabolic pathways and cellular activity lead to neuronal impairment in patients.
    To explore the effects of the GBA mutations, we are using cellular models derived from fibroblasts of two PD patients, harbouring mutations in GBA and mutations in another gene causing of the disease. These fibroblasts, reprogrammed into induced pluripotent stem cells, can be further differentiated to small neuronal precursor cells to finally generate midbrain-specific dopaminergic neurons. Phenotyping these cells in terms of protein expression, lysosomal activity or mitochondrial morphology and function will allow us to understand the molecular basis of GBA effects in PD.Exploring the effects of GBA mutations in the context of monogenic PD with well-known mutations will open new perspectives in the comprehension of combined/additive effects of different genes in the same individual.

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    Familial forms of Parkinson’s disease (PD) offer the opportunity to generate human cell models based on induced pluripotent stem cell (iPSC) technology to study the pathophysiology of the disease. These models are used to identify molecular pathways involved in PD and to gain general insights not only into familial but also into idiopathic PD. One of the causes of familial PD is homozygous loss-of-function mutations of DJ-1. DJ-1, a protein encoded by the gene PARK7, has broad biological functions including effects on mitochondrial and lysosomal homeostasis (Krebiehl et al.). We have previously shown that fibroblasts obtained from PD patients carrying the homozygous mutation c.192G>C in the DJ-1 gene display a phenotype of impaired mitochondrial respiration, increased intra-mitochondrial reactive oxygen species, reduced basal autophagy and the accumulation of defective mitochondria.

    In order to study the effect of DJ-1 loss of function on PD target cells, midbrain-specific dopaminergic (mDA) neurons, astrocytes and microglia, we have generated iPSC from these fibroblasts that are used in state-of-the-art differentiation protocols. Using pairs of disease-specific and isogenic control iPSC we’re identifying cellular phenotypes that can be used as read out for small chemical compound library screens. Furthermore, we are studying the metabolic implications for the cell caused by loss of DJ-1 in PD cell models and caused by DJ-1 upregulation in glioblastoma multiforme cell models.
    Results have been published in Science Translational Medicine in September 2020.

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    Following the discovery that SNCA encodes α-synuclein (Polymeropoulos et al., 1997) in an A53T autosomal dominant form of inheritance in a familial case of PD, a further five other point mutations have been identified in families with hereditary PD: A30P (Kruger et al., 1998), E46K (Zarranz et al., 2004), H50Q, (Appel-Cresswell et al., 2013), G51D (Lesage et al., 2013) and A53E (Pasanen et al., 2014). Furthermore, duplications and triplications of SNCA have been identified leading to the clinical manifestation of the disease, with the triplication of SNCA leading to an earlier disease onset and increased diseased severity. Several Genome Wide Association Study (GWAS) have also implicated the variability at the SNCA locus as a major risk factor in idiopathic PD (Simon-Sanchez et al., 2009). The oligomerisation of the monomeric α-synuclein into toxic aggregates of amyloid-like fibrils is one of the main pathogenic features of α-synuclein, which is a major constituent of LB (Spillantini et al., 1998).
    Our panel of patient-derived iPSC lines include SNCA point mutations (A30P, A53T) or gene copy number alterations (duplication and triplication). We have generated a set of isogenic corrected cell lines and have introduced SNCA point mutations into age- and gender-matched healthy controls. Exploring PD related phenotypes in dopaminergic neuron cultures, our particular focus is on aSyn roles at membranes, e.g. mitochondria/ER and exosomes.
    Based on these phenotypes we are developing assays to screen in high-throughput small molecule libraries for drug discovery and drug repurposing.
    Considering the role of α-synuclein spreading in PD’s pathophysiology, we study the exosomal-based role of α-synuclein and the alterations of the exosomal content (RNAs, DNAs, proteins and metabolites) in different PD-patient iPSC-derived neuronal/glial populations. Validation of the these alterations can lead to the identification of novel PD-related biomarkers, that can be applied for prognostic and diagnostic purposes.

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    The VPS35 D620N mutation has been identified as an autosomal-dominant cause of familial PD. The VPS35 protein is a component of the retromer complex and is implicated in the sorting and trafficking of various proteins from endosomes to the trans-Golgi network. Recent studies have revealed the role of VPS35 in another trafficking pathway from mitochondria to peroxisomes through mitochondria-derived vesicles. The D620N mutation is thought to lead to impaired trafficking of proteins, causing dysfunctions in mitochondria and autophagy.
    The aim of this project is to study the phenotype of midbrain dopaminergic neurons (mDA) and microglia derived from patient’s fibroblasts carrying the VPS35 D620N mutation. We use live cell imaging techniques, biochemical and functional assays to study the impact of the VPS35 D620N mutation on mitochondrial function,protein clearance mechanisms and cell-specific cellular phenotypes.

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    Parkinson’s disease (PD) is the most frequent neurodegenerative movement disorder. While several genes causative for familial forms of PD as well as risks factors have already been identified, it is still unclear how patient’s genomes shape their predisposition to develop PD. For example, despite sharing the same mutation in the LRRK2 gene – the most common cause of late-onset familial PD – carriers display broad variation in severity of symptoms as well as the time of disease onset. To address this observed and unexplained variation, the LCSB takes part in an international effort, collaborating with partners in several European countries, to study families sharing both a history of PD and a G2019S mutation in the LRRK2 gene. By comparing clinical data and genetic profiles of patients a list of susceptibility factors has been generated (ongoing collaboration with Dr. Enrico Glaab and Dr. Patrick May at the LCSB). We are investigating the effects of these susceptibility factors on PD related phenotypes using iPSC derived dopaminergic neuron cultures from PD patients and healthy controls .

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    Parkinson´s disease is most likely caused by a complex interplay between genetic and environmental factors. Many of the genes causing familial forms of PD have been identified, however, the molecular and cellular mechanisms leading to the specific hallmarks of this neurodegenerative disease remain unknown. As mitochondrial dysfunction is a common feature of both familial and idiopathic forms of PD, we carry out a functional analysis of genes underlying mitochondrial dysfunction in PD. Single and combinatorial gene perturbations are applied via gene knockdown and gene overexpression methods in neuronal cell culture models. Subsequently, a number of physiological and pathophysiological processes are analysed, i.e. the mitochondrial membrane potential and turnover, NADH turnover or ROS production. For this purpose, we perform live-cell imaging experiments combined with an automated image analysis pipeline to extract a wide range of features that characterise cellular and organelle function and help to potentially stratify PD into specific mechanism-based subtypes.

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    Epidemiological studies indicate that patients with T2D have an increased risk of developing PD. These two age-related chronic diseases share similar alterations in essential biological processes and molecular networks, suggesting common mechanisms underlying their pathogenesis. Mutations in the mitochondrial kinase PINK1 are the second most frequent cause of autosomal recessive PD. Based on the compelling evidence implicating PINK1 also in T2D, we decided to use complementary PINK1-deficient cellular models (PINK1-mutant iPSC-derived dopaminergic neurons and PINK1-silenced pancreatic β-cells) as prototype to decipher the cellular alterations leading to neurodegeneration in PD and β-cells failure in T2D, trying to clarify the functional interdependencies between the two diseases. Findings obtained from this project will allow the identification of novel potential therapeutic targets, thus contributing to patient-based biomedical research in both fields.

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    Given the large body of evidence pointing to mitochondrial dysfunction and oxidative stress as causative events in PD pathogenesis, mitochondria emerged early as logical targets for disease-modifying treatments in PD, but unfortunately all PD clinical trials applying mitochondrially active drugs to unselected patient groups failed. In this light, genetic stratification of mitochondrial risk could help to define subgroups of idiopathic PD (iPD) patients, who may be more responsive to therapeutic compounds targeting mitochondrial defects. Here, we use computational approaches based on mitochondria-specific polygenic risk scores (mitoPRSs) to assess the synergistic effect of common variants in nuclear-encoded mitochondrial genes on PD risk. Importantly, we functionally validate mitoPRS profiles in cellular models from iPD patients with high or low mitochondrial risk, paving the way for translating genetic prediction into personalized, mitochondrially-targeted, therapeutic treatments.

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    PD patients and healthy subjects are recruited in Luxembourg and the Greater Region. The aim is to improve diagnosis and stratification of PD by developing novel disease biomarkers. This project is funded by the Luxembourg National Research Fund (FNR) anf further information can be found at page 20 flagship programmes.

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    The team participates in a multicentre clinical study on the implementation of novel deep brain stimulation to treat therapy-resistant gait-freezing in advanced PD patients. A novel concept targeting the substantia nigra pars reticulata in the brain is used in a clinical study, supported by Medtronic, comprises 10 centres in Germany and Luxembourg.

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    Our group develops innovative patient care concepts for PD and other conditions. We coordinate ParkinsonNet-Luxembourg, which brings healthcare professionals together and facilitates Parkinson-specific specialisation, interdisciplinary collaboration and exchange of knowledge, allowing that every PD-patient in Luxembourg receives the best possible care. In addition, we lead the Programme Démence Prévention (pdp). The aim of pdp is to implement a programme launched by the Luxembourgish Ministry of Health allowing, by the means of a personalized lifestyle intervention, to prevent, or at least delay, the development of dementia in a target population, defined by a mild cognitive impairment or subjective cognitive decline.

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