Title Abstract "Druwé-Eerdekens & Van Ael and the Vlaamse Parkinson Liga: ""'A Novel Training Method to Reduce Fall Risk in People with Parkinson’s Disease: The Role of the Balance Organ" "geen abstract" "Technology-assisted writing training in Parkinson's Technology-assisted writing training in Parkinson's" "Alice Nieuwboer" "Research Group for Neurorehabilitation (eNRGy)" "The basal ganglia play an important role in motor learning, especially during the consolidation phase. This raises the question whether it is possible to sustain learning increments in a neurodegenerative condition such as Parkinsons disease (PD). The aim of this study is to gain knowledge on whether it is possible to relearn skills which are actually affected by PD, such as writing, and determine whether neuroplasticity is possible. In this randomized controlled study, PD patients will either follow intensive writing training or a placebo treatment (stretch and relaxation training) during 6 weeks. The writing training will focus on automatization (withstanding dual task interference), transfer to an untrained task and retention. The placebo program is aimed to reduce stiffness in the upper limbs and has been shown to be ineffective in PD. To date, it is unknown how neural networks change as a result of consolidation after a prolonged period of motor learning in PD. Therefore the second arm of this study will investigate, for the first time, changes in neural connectivity using brain imaging data to elucidate which neuroanatomical regions are involved in consolidation of learning in PD. Finally, DTI andresting state fMRI-analysis will complement insights into the neural changes as a result of learning." "Do cognitive problems underlie motor deficits in Parkinson's Disease?" "Wim Notebaert" "Department of Experimental psychology" "ParkinsonU+2019s disease (PD) is characterized by motor symptoms such as tremor (for example, involuntarily shaking of a patientU+2019s leg) and postural instability. In addition, PD patients have difficulty learning new movement patterns. In this project, we will examine whether these motor problems may relate to problems in cognitive functioning. We will also study the role of medication in this relationship." "The effects of Closed-Loop Auditory Stimulation during Sleep on sleep quality and motor learning in Parkinson’s disease" "Moran Gilat" "Research Group for Neurorehabilitation (eNRGy)" "Sleep facilitates motor learning and is critical for our health. People with Parkinson’s disease (PD) suffer from sleep problems that severely affect their wellbeing. Poor sleep also impairs motor learning, which hampers rehabilitation effects. We thus want to test whether closed-loop auditory stimulation can improve sleep while at the same time facilitate motor learning in PD. If proven effective, two main problems are addressed with an automated solution that requires no effort of the patient." "Spinal Cord Stimulation for Freezing of Gait in Parkinson's Disease" "Philippe De Vloo" "Research Group Experimental Neurosurgery and Neuroanatomy" "Our project aims to define the outcome, safety, optimal stimulation paradigm and underlyingmechanism of spinal cord stimulation (SCS) on Freezing of Gait (FOG), one of the mostdisabling Parkinson's Disease symptoms that is often poorly responsive to current therapies. We will not only assess the effect of SCS on FOG in a randomized double-blind on/off crossover design but also acquire electrophysiological data directly from the brain and spinal cord during freezing-provoking tasks." "A profound study of gut homeostasis in Parkinson's disease." "Department of Internal Medicine and Pediatrics, Department of Biomedical molecular biology" "ParkinsonU+2019s disease (PD) is the second most common neurodegenerative disorder and due to the lack of early diagnosis and effective therapy, represents a large burden for our society and healthcare system. The last years, it became increasingly apparent that non-motor symptoms, including gastrointestinal dysfunction, precede the onset of the typical PD motor symptoms by over two decades. Moreover, emerging evidence suggests that PD, and more specifically the aggregation of alpha-synuclein syn), starts in the gut before spreading to the brain. Additionally, recent microbiome studies consistently showed microbiota differences between PD patients and healthy controls. However, detailed insights in how the microbiome affects the patientsU+2019 symptoms is lacking. The ultimate goal of this project is to address the impact of gut dysbiosis and the restoration of gut homeostasis by fecal microbiota transplantation (FMT) on the development and progression of PD. We will identify PD-specific changes in microbiota composition and gut inflammation and determine the effect of a U+2018microbiome-resetU+2019 approach through FMT in PD patients on the identified changes and more importantly on disease symptoms and progression. In parallel, we aim to elucidate the mechanism by which the microbiome affects PD disease onset and progression, using a mouse model of PD, focusing on the effect of the microbiome on syn expression, aggregation and spreading." "Customized nutrition for Parkinson's disease patients" "Christophe Matthys" "Clinical and Experimental Endocrinology" "Parkinson's disease is the second most prevalent neurodegenerative disorder, characterized by both motor and non-motor deficits. It's cause has not yet been elucidated and no treatment has yet been discovered. The current therapies predominantly relieve motor symptoms. The non-motor deficits include sensory symptoms such as the loss of taste and smell, but also various gastro-intestinal symptoms, including dysphagia, nausea and bloating. In these symptoms diet could play a role in symptom relief. The objective of this research project is to evaluate the potential role of a customized diet as an adjuvant therapy in Parkinson's disease This was achieved by through 2 research lines. The first research line involves the direct impact of diet on Parkinson's disease, with a focus on the use of thickened liquids in dysphagia and the identification of food odors by hyposmic patients. Bolus modification is one of the management strategies of dysphagia, which consists of softening solids and thickening liquids to ensure safe swallowing. There are already different thickening agents on the market, both starch- and gum-based, however, they have a negative impact on taste and texture. This results in aversion of patients towards the therapy and low treatment compliance. The objective is to improve the taste, aroma and texture of thickened liquids. This may lead to a higher compliance and consequently an improved quality of life. Parkinson's patients often already suffer from hyposmia, impacting the flavor perception of food and reducing patients' quality of life. Identification of food odorants that are well recognized by Parkinison's patients may aid in the development of aroma boosters.The second research line involves the indirect impact of diet, herein we take a closer look at the involvement of the gut-brain axis in the pathology of Parkinson's disease and the possible use of food-based therapies. The bacterially-produced short chain fatty acids are implied to have beneficial effects in Parkinson's disease, however short chain fatty acid-producing bacteria are reduced in Parkson's patients. The objective is to stimulate short chain fatty acid production in vitro in fecal samples of Parkinson's patients, using different types of dietary fiber. " "Analysis of the role of the Parkinson's disease-linked protein DJ-1 in mitophagy" "Wim Vandenberghe" "Laboratory for Parkinson Research" "Parkinson’s disease is a very common brain disease characterized by slowness of movement, tremor, falls, dementia and many other problems. There is still no therapy that slows down its relentless progression. In Parkinson’s disease dopamine-producing nerve cells in the brain gradually die. Why these cells die, is not well understood. In some familial cases Parkinson’s disease is caused by genetic mutations. Rare mutations in the genes for parkin, PINK1 and DJ-1 all cause a particular subtype of Parkinson’s disease with specific clinical and genetic characteristics. Parkin and PINK1 are crucial for the maintenance of a healthy pool of mitochondria in the cell. Mitochondria are organelles that produce energy but, when damaged, can induce cell death. Sick mitochondria must therefore be eliminated if the cell is to survive. When mitochondria become damaged, Parkin and PINK1 cooperate to label them for selective destruction, a process called mitophagy. Parkinson mutations in the genes for parkin and PINK1 disrupt mitophagy. Very recently, we have found that DJ-1 is also required for mitophagy. In this project, we will unravel the mechanisms by which DJ-1 mediates mitophagy. We will investigate this in skin cells from Parkinson’s disease patients with DJ-1 and parkin mutations and from healthy controls, in neurons derived from these skin cells and in fruit fly models. This work may identify new molecular targets for future therapies to slow down the course of the disease." "Pathogenic mechanisms of GCH1-associated Parkinson's disease" "Wim Vandenberghe" "Laboratory for Parkinson Research" "Parkinson’s disease is a common brain disease characterized by slowness of movement, tremor, falls, dementia and many other problems. There is still no therapy that slows down its relentless progression. In Parkinson’s disease dopamine-producing nerve cells in the brain gradually become sick and eventually die. Why these cells die, is not well understood. In rare familial cases Parkinson’s disease is caused by genetic mutations. Recently, it was discovered that mutations in the GCH1 gene strongly increase the risk of developing Parkinson’s disease. GCH1 codes for the enzyme GTP cyclohydrolase 1, which is required for the synthesis of tetrahydrobiopterin. Tetrahydrobiopterin is necessary for the production of dopamine, but also protects cells against damaging oxygen radicals. Parkinson’s disease-associated GCH1 mutations impair the ability to synthesize tetrahydrobiopterin, but how this leads to Parkinson’s disease is currently unknown. In this project we will investigate the mechanisms by which GCH1 mutations induce death of dopaminergic neurons. We will analyze the role of GCH1 and tetrahydrobiopterin in cellular health and survival in skin cells from patients with GCH1 mutations and healthy controls, in dopaminergic neurons derived from these skin cells and in dopaminergic neurons in the brains of fruit flies. Understanding the molecular link between GCH1 mutations and Parkinson’s disease will hopefully contribute to the development of better therapies." "Insight in the molecular consequenses of LRRK2 kinase inhibition, a kinase involved in Parkinson's disease." "Veerle Baekelandt" "Research Group for Neurobiology and Gene Therapy" "Parkinson’s disease is the second most common neurodegenerative disorder, after Alzheimer’s disease, and the most common movement disorder. Worldwide, 7 to 10 million people suffer from Parkinson’s disease. It is estimated that this number will only increase due to the general ageing of the population, as the disease primarily affects people older than the age of 60. Current therapies fail to cure, halt or slow down disease progression, partly because the exact etiology of Parkinson’s disease is still poorly understood. However, treatment options that are able to (temporarily) suppress a patient’s symptoms do exist.Since 1997, different genetic studies revealed that mutations in several genes underlie the development of Parkinson’s disease. To date, mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common known cause of genetic forms of Parkinson’s disease. Moreover, the clinical phenotype of patients carrying LRRK2 mutations strongly resembles the phenotype of patients with a sporadic form of the disease, which might indicate a common etiology. Consequently, more insight in the molecular processes that underlie the development of genetic Parkinson’s disease could provide important insights for the development of potential new therapies, both for genetic and sporadic forms of the disease.For example, studies have shown that pathogenic mutations in LRRK2 display increased kinase activity. As a result, kinase inhibition was proposed as a potential therapeutic strategy. Studies in cell culture and in animal models, both LRRK2-based and non-LRRK2-associated PD models, have shown the protective effect of LRRK2 kinase inhibition. Regardless, some caution is warranted, as we might not yet fully comprehend all the consequences of LRRK2 kinase inhibition.First of all, LRRK2 kinase inhibition induces dephosphorylation of the LRRK2 protein, which is also seen in pathogenic LRRK2 variants. This finding indicates a potential contribution of dephosphorylation to LRRK2 pathogenesis in Parkinson’s disease. Signal transduction in a cell or between cells often relies on whether or not certain proteins are phosphorylated. It is of great importance to identify the different phosphatase complexes involved in LRRK2 dephosphorylation after LRRK2 kinase inhibition or in pathogenic conditions. Our lab identified the catalytic subunit of protein phosphatase 1 (PP1) as the phosphatase acting on pathogenic variants of LRRK2 and during LRRK2 kinase inhibition. The regulatory proteins or other phosphatases involved in the process, remain elusive. In the first part of this work, we aimed to identify phosphatases or regulatory proteins involved in LRRK2 dephosphorylation after LRRK2 kinase inhibition. Therefore, a small interfering (si) RNA screen was executed, in which the effects on LRRK2 phosphorylation were investigated after knockdown of specific phosphatases or regulatory proteins. In this project, we aimed to further validate the top hits from the siRNA screen in cells, using lentiviral vector-mediated knockdown. Besides PP1, we found that also the protein phosphatase 2A (PP2A) complex is involved in the LRRK2 dephosphorylation cycle, especially after LRRK2 kinase inhibition. Further identification of the LRRK2-phosphatase complex in pathogenic variants or after kinase inhibition, will provide more insight in potential therapies for Parkinson’s disease.Besides, we and others found that prolonged treatment with LRRK2 kinase inhibitors causes a decrease in total LRRK2 protein levels. This could be observed both in cell culture and in animals treated with LRRK2 inhibitors. A characteristic pathology has been described in the lung of inhibitor-treated animals. Moreover, this phenotype was also observed in LRRK2 knockout animals. In the next part of this work, we aimed to identify the underlying mechanism of LRRK2 kinase inhibitor-induced destabilization. By studying and/or blocking the different ways for synthesis or degradation of proteins in the cell, we found that LRRK2 is mainly degraded by the proteasomal system after LRRK2 kinase inhibition. Next, we aimed to further characterize LRRK2 kinase inhibitor-induced destabilization in different pathogenic LRRK2 mutants. We observed that not all pathogenic variants of LRRK2 show a decrease in total LRRK2 protein levels after treatment. Remarkably, mutants that are strongly dephosphorylated, do not destabilize after LRRK2 kinase inhibition, in contrast to an only partly dephosphorylated mutant. Consequently, we assumed that the basal phosphorylation levels of the LRRK2 protein could be important in the regulation of protein homeostasis and induction of destabilization. We investigated the importance of already known phosphorylation sites, by mutating these residues. We found that none of the already known phosphorylation sites were crucial residues in the induction of protein degradation. Casein kinase 1α (CK1α) was identified as the kinase phosphorylating these known, and potentially other unknown, phosphorylation sites in LRRK2. After inhibition of CK1, destabilization of the LRRK2 protein still occurs, both in wild type LRRK2, in pathogenic LRRK2 variants, in the LRRK2 variant in which we mutated known phosphorylation sites and in the lung in mice. Consequently, we hypothesize that currently unknown phosphorylation sites, regulated by CK1, could be the primary inductors of LRRK2 kinase inhibitor-induced destabilization of LRRK2. The next crucial step is the further identification of this/these phosphorylation site(s). The second part of the study offers important new insights in the protein homeostasis of LRRK2, which will contribute to a broader knowledge on the working mechanism of LRRK2 kinase inhibitors, one of the prevailing therapeutic strategies for the treatment of Parkinson’s disease nowadays."