Research Rosa Rademakers

Abstract

TMEM106B haplotypes have been identified as risk factors for several neurodegenerative diseases such as Frontotemporal Lobar Degeneration with TDP-43 aggregates (FTLD-TDP) and Alzheimer's Disease (AD) and healthy aging, suggesting that they determine neuronal vulnerability. These haplotypes regulate expression of TMEM106B, a lysosomal type-II transmembrane protein, being the risk haplotype causative of a slight expression increase. In this project I hypothesize that subtle changes in TMEM106B expression condition neuronal fitness by dysregulating lysosomal physiology. To study this, I will generate isogenic PSC-derived cortical neurons with different TMEM106B expression levels: a full knockout (TMEM106B-/-) and an inducible-reversible overexpression (TMEM106BOE) model. These will be transplanted in the brains of AppNL-G-F and Grn-/- mice as models of AD and FTLD-TDP, respectively, to analyze how a neurodegenerative environment affects neurons in a TMEM106B expression-dependent manner. Lastly, I also aim to perform an in depth characterization of the lysosomes in these neurons in vitro by analyzing their proteome, trafficking, activity, size and localization and validating these results in the transplanted brain slices. Overall, this project aims to shed light into the molecular mechanism through which TMEM106B expression regulates neuronal vulnerability to disease by integrating neuropathological outcomes observed in the transplanted neurons with lysosomal dysfunctions.

Researcher(s)

• Promoter: Rademakers Rosa
• Co-promoter: Mancuso Renzo
• Fellow: Lastra Osua Miranda

Research team(s)

• VIB CMN - Applied and Translational Neurogenomics

Project type(s)

• Research Project

Abstract

Neurodegenerative diseases are a growing burden to patients, our society, and the healthcare system, yet therapeutic breakthroughs remain limited despite intense research. We investigate the genetic factors of frontotemporal dementia to identify critical factors involved early in the disease's process, as half of the patients are without a genetic diagnosis and without targets for (precision) therapy. Here I propose to tackle this issue from two angles, focusing on 1) tandem repeat length variation and expansions and 2) somatic variants in the brain. There is evidence of the involvement of both types of variants, but systematic assessments are necessary to determine their contribution to FTD. A crucial part of this project concerns the development of software for genome-wide characterization of tandem repeat variation and a database for population-scale repeat lengths. This research has only recently become possible, as novel sequencing technologies are now well-established for population-scale projects. I will investigate both causal and risk-associated roles for tandem repeat expansions using short and long-read sequencing cohorts. In addition, I will follow up on somatic single-nucleotide variants using long-read single-nuclei transcriptomics and identify somatic structural variants using deep genome sequencing from sorted neurons. Finally, target capture of cell-free DNA in plasma and CSF will be explored as a biomarker for the early detection of neurodegeneration.

Researcher(s)

• Promoter: Rademakers Rosa
• Fellow: De Coster Wouter

Research team(s)

• VIB CMN - Applied and Translational Neurogenomics

Project type(s)

• Research Project

Abstract

Frontotemporal lobar degeneration (FTLD) represents a heterogeneous group of neurodegenerative disorders that progressively disrupt core human characteristics. FTLD accounts for 10-20% of all young-onset dementias. The atrophy in frontotemporal brain regions is caused by abnormal accumulation of disease proteins, such as TDP-43. In 2010, variants in TMEM106B were identified as the first common genetic risk factor for FTLD and as the most important modifier of disease risk in patients with progranulin (GRN) mutations (FTLD-GRN). More recent studies also implicate TMEM106B in multiple brain disorders and aging as well as a disease modifier in cancer and Covid-19. The involvement of this lysosomal protein TMEM106B in this wide variety of diseases highlights the need to improve our understanding of TMEM106B biology and function. In this project, we will perform an in-depth characterization and explore the role of TMEM106B in vesicle trafficking (endo- and exocytosis) and extracellular vesicle biology. By modulating these pathways, variations in TMEM106B could mediate the spreading of disease proteins. In this context, we will investigate the role of TMEM106B in FTLD-GRN and study the underlying disease interaction between TMEM106B and GRN. Our findings will also have value beyond the scope of neurodegeneration by contributing to our basic understanding of TMEM106B and its role in the endolysosomal pathway and could potentially lead towards new therapeutic avenues.

Researcher(s)

• Promoter: Rademakers Rosa

Research team(s)

• VIB CMN - Applied and Translational Neurogenomics

Project type(s)

• Research Project

Abstract

Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a heterogeneous neurodegenerative disorder. Patients present with severe disturbances in personality, behavior or language and die within a few years. Identification of two major FTLD-TDP genes (progranulin (GRN) and C9orf72) provided important insight into possible disease mechanisms and led to recently started clinical trials in genetic FTLD-TDP subtypes. However, for patients without known mutations, mechanisms of disease remain poorly understood with no hope for treatment. We hypothesize that a subgroup of FTLD-TDP patients without known mutations (FTLD-TDP type A) share common disease mechanisms with GRN mutation carriers and could benefit from the treatments that are in development. Here, we will use long-read whole-genome DNA sequencing, able to capture genomic and epigenomic alterations, to identify hitherto undiscovered disease-associated mutations in FTLD-TDP type A patients (WP1). Long-read cDNA sequencing and single-nuclei transcriptomics will be performed to correlate expression changes with possible disease-contributing variants and to provide additional insight into FTLD-TDP type A disease pathways (WP2). Finally, we will assess the value of translation products from differentially expressed genes or FTLD-TDP type A specific transcripts as fluid biomarkers (WP3). These studies will improve the biological understanding, diagnosis and potential for future treatment of FTLD-TDP type A patients.

Researcher(s)

• Promoter: Rademakers Rosa
• Co-promoter: De Coster Wouter

Research team(s)

• VIB CMN - Applied and Translational Neurogenomics

Project type(s)

• Research Project

Abstract

The primary mission of the Neuromics Support Facility (NSF) is to provide technological support and services in its core fields of expertise: long- and short-read sequencing, optionally followed by streamlined data analysis. Subsidised as a UA Core Facility since 2007 with the initial assignment of providing high quality Sanger sequencing services, NSF has since evolved into a much needed center of competence, offering affordable support with cutting-edge genomic technology. Since its inception, NSF has provided support to over 40 different UA groups and collaborated with over 230 research groups and companies. Embedded in the Center for Molecular Neurology (CMN) and affiliated with the Faculty of Pharmaceutical, Biomedical and Veterinary Sciences (UA) and VIB, NSF is optimally positioned to offer support in life science research, and understands and caters to the needs of diverse research groups. NSF was established in 2017 by merging the Genetics Support Facility (GSF) with central support in data analysis and imaging, to centralise the existing expertise. In 2017, NSF also expanded its services and is now supporting a variety of sought-after, wet- and dry- lab applications, including sequencing, quality control, sample prep, library prep and data analysis, using standardised in-house analytical pipelines. As a UA Core Facility, NSF will continue to provide extensive expertise to the researchers across UA, VIB and third party collaborators and will continue collaborating, consulting and troubleshooting in all their proficiencies for a very affordable fee for UA affiliates.

Researcher(s)

• Promoter: Rademakers Rosa
• Co-promoter: Sleegers Kristel
• Co-promoter: Strazisar Mojca

Research team(s)

• VIB CMN - Applied and Translational Neurogenomics

Project website

Project type(s)

• Research Project

Abstract

Frontotemporal lobar degeneration (FTLD) is an early-onset form of dementia representing 10-20% of all dementia cases. It is characterized by the loss of neurons in the frontal and temporal lobes resulting in a dramatic impact on core human qualities including personality, insight and verbal communication. Aggregates of the TAR DNA-binding protein 43 (TDP-43) are the hallmark of the most common pathological subtype of FTLD (FTLD-TDP). Importantly, over the past decade, the field of neurodegeneration has shifted from a proteinopathy-centric view towards the concept of a multicellular hypothesis underlying both initiation and perpetuation of disease. Genetic studies have helped significantly in deciphering the cellular substrate of neurodegeneration. In relation to FTLD, the Rademakers lab identified loss-of-function mutations in progranulin (GRN) as one of the major genetic causes of FTLD. They also described TMEM106B genetic variants as the first genetic risk factor for FTLD-TDP and found that TMEM106B protective variants can dramatically reduce the disease penetrance of GRN mutations. GRN and TMEM106B are enriched in separate cellular compartments (microglia versus neurons, respectively), depicting a scenario where different genetic factors interact from multiple cellular compartments. We hypothesise that the genetic risk shapes cellular responses and phenotypes promoting particular disease states in microglia which modify the vulnerability of neurons to degeneration. We propose to investigate this concept in the context of FTLD and age-related TDP-43 neuropathology using the established disease genes GRN and TMEM106B in microglia and neurons, respectively. However, the study of genotype-phenotype interactions in neurodegeneration is not trivial, as there is a limited homology between human and mouse in terms of expression of disease associated genes. To overcome this limitation, the Mancuso lab has developed a model of human iPSC-derived brain cells xenotransplantation to study human relevant genetic traits in a diseased mouse brain environment. In a joined effort from the Rademakers and Mancuso labs, we here propose to investigate the impact of GRN and TMEM106B genetic variants by iPSC microglia and neurons derivation, and xenotransplantation, in FTLD (Grn-/-) and wild type mice. We plan to 1) generate isogenic series of iPSC lines containing GRN and TMEM106B mutations; 2) determine the impact of GRN deficiency in human microglia and determine whether this deficiency is sufficient to induce neuropathology in the mouse brain; and 3) determine if changes in TMEM106B expression in human neurons lead to susceptibility or resilience against degeneration, in vivo. Our studies will provide critical knowledge on the diverse cellular processes underlying FTLD and we expect the novel insights gained from this research to be invaluable for the development of novel therapeutic strategies for FTLD patients and related disorders.  

Researcher(s)

• Promoter: Rademakers Rosa
• Co-promoter: Mancuso Renzo

Research team(s)

• VIB CMN - Applied and Translational Neurogenomics

Project type(s)

• Research Project

Abstract

Frontotemporal lobar degeneration (FTLD) represents a heterogeneous group of neurodegenerative disorders that progressively disrupt core human characteristics. FTLD accounts for 10-20% of all young-onset dementias. The atrophy in frontotemporal brain regions is caused by abnormal accumulation of disease proteins, such as TDP-43. In 2010, variants in TMEM106B were identified as the first common genetic risk factor for FTLD and as the most important modifier of disease risk in patients with progranulin (GRN) mutations (FTLD-GRN). More recent studies also implicate TMEM106B in multiple brain disorders and aging as well as a disease modifier in cancer and Covid-19. The involvement of this lysosomal protein TMEM106B in this wide variety of diseases highlights the need to improve our understanding of TMEM106B biology and function. In this project, I will perform an in-depth characterization and explore the role of TMEM106B in vesicle trafficking (endo- and exocytosis) and extracellular vesicle biology. By modulating these pathways, variations in TMEM106B could mediate the spreading of disease proteins. In this context, I will investigate the role of TMEM106B in FTLD-GRN and study the underlying disease interaction between TMEM106B and GRN. Our findings will also have value beyond the scope of neurodegeneration by contributing to our basic understanding of TMEM106B and its role in the endolysosomal pathway and could potentially lead towards new therapeutic avenues.

Researcher(s)

• Promoter: Rademakers Rosa
• Fellow: Perneel Jolien

Research team(s)

• VIB CMN - Applied and Translational Neurogenomics

Project type(s)

• Research Project

Abstract

Frontotemporal lobar degeneration (FTLD) is an umbrella term that groups several different neurodegenerative diseases characterized by the predominant destruction of the frontal and temporal lobes of the brain. In this proposal we focus our efforts on a relatively rare subgroup of FTLD patients which have an unusual clinical phenotype and a uniform pathology characterized by FTLD with neuronal inclusions composed of the fused in sarcoma (FUS) protein (FTLD-FUS). More than a decade after its initial description no progress has been made towards understanding the etiology of this subgroup of patients, thus severely hampering translational research efforts. To fill this void, we established the international consortium on FTLD-FUS. Through the systematic collection of brain tissue samples and associated clinicopathological data from the majority of reported FTLD-FUS patients we will for the first time be in a position to decipher its molecular underpinnings. Based on its unique clinical and pathological features, we hypothesize that FTLD-FUS is caused by genomic or epigenomic mutations in one or a limited number of disease genes. The overall objective of this proposal is to identify these genetic and/or epigenetic factors through the study of our unique, highly characterized, cohort of FTLD-FUS patient samples and state-of the art methodologies able to capture a broad range of possible genomic and epigenomic alterations. This will include NanoNOMeseq to identify phased methylation and chromatin accessibility as well as genetic changes such as structural variations from a single assay. Deep transcriptomic profiling at the single cell level and bulk analyses of full-length transcripts using long-read sequencing technologies in brain tissues of FTLD-FUS patients and controls will further be generated to correlate expression changes with possible disease-contributing variants and to provide much needed insights into the FTLD-FUS associated disease pathways. The identification of disease causing or disease modifying factors for FTLD-FUS will be crucial for elucidating the pathogenetic mechanisms underlying this subgroup of FTLD patients and ultimately for the development of curative therapies.

Researcher(s)

• Promoter: Rademakers Rosa
• Co-promoter: De Coster Wouter
• Fellow: Alidadiani Sara

Research team(s)

• VIB CMN - Applied and Translational Neurogenomics

Project type(s)

• Research Project

Abstract

Frontotemporal Degeneration (FTLD) is a group of diseases that is remarkable for the loss of brain cells in the temporal and frontal lobes of the brain. FTLD comprises 10-20% of all dementias and presents relatively early in life, around the ages of 45-60. It has a negative effect on the quality of life, affecting personality, insight, verbal communication, social behavior, and cognition, with progressive deterioration in all of these characteristics. An additional feature is the progressive language deterioration involving the impairment of speech and the inability to understand words or name objects, and some patients also present with Parkinson-like movement disorders. Upon brain autopsy, different proteins are found in the affected brain areas of patients, with most patients showing accumulations of the Tau or the TDP-43 proteins. One major obstacle in the treatment of FTLD is the difficulty to identify the specific disease protein that is accumulating in a patient's brain during life. Some clinical presentations have a high likelihood of predicting the underlying pathology but others, including the most common clinical syndrome characterized by behavioral and personality changes, do not. Since it is expected that FTLD patients with Tau and TDP-43 accumulations need distinct treatments, and such treatments are currently being actively pursued, biomarkers that are able to distinguish these two major pathological subtypes are urgently needed. The goal of this project will be to discover new FTLD biomarkers using advanced mass spectrometry analysis of blood plasma and cerebrospinal fluid samples. This project will be enabled through unique and secured access to FTLD patient samples and innovative approaches to identify FTLD-specific proteins. The proposed research will bring the field closer to clinically-relevant biomarker signatures for FTLD that separate between FTLD-TDP and FTLD-Tau patients. Upon completion of this project, researchers and clinicians will be able to better stratify patients between types of FTLD in clinical trials. This will allow for tailored results, and the development of specific therapies, based on the specific proteins pathology of the disease. Ultimately, the goal will be to identify the best possible candidate biomarkers for further development into clinical biomarkers that can be used to treat patients with tailored therapeutics.

Researcher(s)

• Promoter: Rademakers Rosa

Research team(s)

• VIB CMN - Applied and Translational Neurogenomics

Project type(s)

• Research Project

Abstract

Yearly funds from BOF to support the maintenance of the collective infrastructure of the VIB Center for Molecular Genomics. These include specialized equipment and robots from our Neuromics Service facility, our cell culture suite and biobank.

Researcher(s)

• Promoter: Rademakers Rosa

Research team(s)

• VIB CMN - Applied and Translational Neurogenomics

Project type(s)

• Research Project

Abstract

This funding is linked to my Professorship as ZAP-BOF to support my broad research in the area of frontotemporal dementia and related disorders. Our research is focused on the identification of causal genes and genetic risk factors and the subsequent functional characterization of novel disease genes with the goal to identify novel targets for therapies and potential biomarkers.

Researcher(s)

• Promoter: Rademakers Rosa
• Fellow: Rademakers Rosa

Research team(s)

• VIB CMN - Applied and Translational Neurogenomics

Project type(s)

• Research Project

Abstract

Research in our group is focused on the discovery and functional characterization of novel disease genes implicated in Frontotemporal dementia (FTD) and related disorders. Together our findings provide new insight into the pathomechanisms underlying FTD and contribute to the development of biomarkers and to the identification new targets for neurodegenerative disease therapies. While significant progress has been made in recent years, its diagnosis can be challenging and no treatments to slow or stop disease progression exist, highlighting the enormous unmet medical need of FTLD patients. Several genes including GRN and C9orf72 are associated with FTLD explaining less than 50% of the patient population. Importantly, even in patients with GRN and C9orf72 mutations, clinical research has demonstrated that the age at symptom onset and clinical phenotype is highly variable and disease penetrance incomplete, creating a significant challenge for counseling of FTLD patients and their asymptomatic relatives. In that context, we recently showed that genetic variants in and around the gene encoding transmembrane protein 106 B (TMEM106B) are able to modify disease onset and/or presentation in such patients. The overarching hypothesis is that insights derived from understanding the genetic basis of FTLD will lead to the elucidation of pathways underlying neurodegeneration. In order to obtain a comprehensive understanding of disease mechanisms, we need to generate multi-omics data including genetics, epigenetics and proteomics at the tissue and single cell levels. In our Research Program, we aim to identify and validate new candidate genes/pathways using large cohorts of patients and controls. In-depth functional characterization is subsequently performed in cellular models using state of the art technologies.

Researcher(s)

• Promoter: Rademakers Rosa

Research team(s)

• VIB CMN - Applied and Translational Neurogenomics

Project type(s)

• Research Project

Abstract

Frontotemporal lobar degeneration (FTLD) groups several neurodegenerative diseases characterized by the progressive degeneration of the frontal and temporal lobes of the human brain. Patients suffer from severe disturbances in personality, behavior or language and die within a few years, as so far no treatment is available. This project is aimed at uncovering the molecular cause of a rare subgroup of FTLD with a uniform pathology characterized by neuronal inclusions containing the fused in sarcoma (FUS) protein (FTLD-FUS). More than a decade after its initial description we only have a very limited understanding of the etiology of this disease subtype, thus severely hampering translational research efforts. To fill this knowledge gap, we established the international consortium on FTLD-FUS and collected brain tissue samples and associated clinicopathological data from FTLD-FUS patients with the goal to decipher its molecular underpinnings. State-of the art methodologies, including the recently developed NanoNOMeseq, will be used to capture a broad range of possible genomic and epigenomic alterations. Single nuclei sequencing and bulk analyses of full-length transcripts using long-read sequencing will also be performed. Proteomic analysis will provide much needed insights into disease mechanisms by uncovering disease-associated changes in protein solubility and post-translational modifications. We will also develop the first human induced pluripotent stem cell models from FTLD-FUS patients to enable future translational studies. The identification of disease causing or modifying factors will lead to a molecular understanding of FTLD-FUS and will greatly enhance our ability to develop novel treatments for patients.

Researcher(s)

• Promoter: Rademakers Rosa

Research team(s)

• VIB CMN - Applied and Translational Neurogenomics

Project type(s)

• Research Project

Abstract

Structural variation accounts for the majority of the nucleotide diversity between humans, yet is systematically underrepresented using current technologies. We can identify about 25000 structural variants per genome with long-read nanopore sequencing, which we will perform in a discovery cohort of 200 control individuals and patients with frontotemporal dementia or Alzheimer's disease. I will optimize structural variant calling and the detection of expanded repeats and single nucleotide variants in highly repetitive sequences. By careful selection of this discovery cohort, we will be able to identify rare and more frequent structural variants explaining association signals from existing cohort studies or underlying disease in small families. In the next phase, the identified variants from longread sequencing will be genotyped in existing data from short-read genome sequencing of 20000 individuals with neurodegenerative brain diseases and healthy controls using recently developed graph genome methods. With association tests on the identified structural variants, I will be able to identify variants with a role in neurodegenerative diseases. Finally, as nanopore sequencing also identifies modified nucleotides I will quantify methylcytosine, per parental haplotypes. I will integrate this with existing data from RNA and protein expression studies and the identified variants, enabling a better functional understanding and identification of cis-regulatory variants.

Researcher(s)

• Promoter: Rademakers Rosa
• Fellow: De Coster Wouter

Research team(s)

• VIB CMN - Applied and Translational Neurogenomics

Project type(s)

• Research Project

Abstract

This project aims to upgrade the current electrophysiology technologies at UAntwerpen by acquiring a state-of-the-art MicroElectrode Array platform (MEA). To study the electrophysiological properties of excitable cells, currently patch-clamping is the gold standard. However, this is an extremely labour-intensive and invasive technique, limited to short-term measurements of individual cells at single time points. On the other hand, MEAs enable high-throughput non-invasive longitudinal real‐time measurements of functional cellular networks, without disrupting important cell-cell contacts, and thus provide a more physiologically relevant model. The multi-well format allows repeated recordings from cell cultures grown under various experimental conditions, including the opportunity to rapidly screen large drug libraries. Based on these advantages, multi-well MEAs are the most suitable instrument for functionally elucidating the pathomechanisms of neurological/cardiac disorders by performing (1) cardiac activity assays: measurement of field and action potentials from (iPSC-)cardiomyocytes to investigate wave-form, propagation and irregular beating; (2) neural activity assay based on three key measures: frequency of action potential firing, synchrony as measure for synaptic strength and oscillation as hallmark for neuronal organization in time; (3) (iPSC-)vascular smooth muscle contractility assay based on impedance alterations.

Researcher(s)

• Promoter: Loeys Bart
• Co-promoter: Kooy Frank
• Co-promoter: Labro Alain
• Co-promoter: Ponsaerts Peter
• Co-promoter: Rademakers Rosa
• Co-promoter: Snyders Dirk
• Co-promoter: Timmerman Vincent
• Co-promoter: Weckhuysen Sarah

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

Crucial insights in cell and developmental biology have been gained by virtue of live cell imaging technology. Along with a growing complexity of cellular models and the finesse with which they can be genetically engineered, comes a demand for more advanced microscopy. In brief, modern comprehensive cell systems research (cellomics) requires light-efficient, intelligent and interactive imaging modalities. To address this shared need, our consortium has identified a state-of-the art platform that allows ultrafast, yet minimally invasive imaging of small to medium-sized biological samples (from single cells to organoids) at high resolution, so as to capture dynamic events that range in timescale from voltage fluctuations to successive cell divisions. To only focus on those events that are truly of interest, and thereby boost throughput, the system is equipped with online image recognition capabilities. Finally, to allow targeted perturbations such as local damage induction or optogenetic switching, small regions can be selectively illuminated in the field of view. With this level of control, it will become possible to interrogate (sub-)cellular processes with unprecedented detail. The platform readily finds applications in diverse frontline research fields including neuroscience, cardiovascular research and infectious diseases, rendering it an indispensable asset for the applicants, the microscopy core facility and the University of Antwerp.

Researcher(s)

• Promoter: De Vos Winnok
• Co-promoter: Caljon Guy
• Co-promoter: De Meyer Guido
• Co-promoter: Jordanova Albena
• Co-promoter: Rademakers Rosa
• Co-promoter: Timmerman Vincent
• Co-promoter: Timmermans Jean-Pierre
• Co-promoter: Vissenberg Kris
• Co-promoter: Weckhuysen Sarah

Research team(s)

• Laboratory of cell biology and histology

Project type(s)

• Research Project

Abstract

The overarching goal of the Genetics Core is the accurate and timely generation, annotation, interpretation and sharing of state-of-the art genetic data on all frontotemporal lobar degeneration (FTLD) patients and blood relatives enrolled in ARTFL LEFFTDS Longitudinal FTLD (ALLFTD) to support FTLD research within and outside of the ALLFTD Program. Genetic characterization of this unique cohort is critically important to test hypotheses and interpret research findings obtained in the other ALLFTD Cores and Projects and will be invaluable to future FTLD gene discovery efforts within the larger research community. The work proposed in this Core is highly complementary and non-overlapping with currently ongoing NIH-funded FTLD sequencing efforts, which will be leveraged to enhance the genetic characterization of our participant cohorts. More than 1,100 unique individuals have been enrolled in ARTFL and LEFFTDS since their inception in 2014 and an additional 1,600 unique individuals are expected to be enrolled as part of the ALLFTD protocol. Consequently, DNA of at least 2,700 individuals will be available for genetic studies, making this an unprecedented resource. Most notably, on all 2,700 subjects, the Genetics Core will: generate genome-wide single nucleotide variant (SNP) data; perform targeted mutation screening of ~300 neurodegenerative disease genes; determine presence or absence of causal mutations in known disease genes; and integrate genetic data in the form of polygenic risk scores (PGRS) for downstream analyses in the Projects. These important goals are achieved through the following Specific Aims: 1) Perform genetic analyses to determine ethnicity and relatedness between ALLFTD participants. Genotyping using the Infinium Omni2.5Exome-8 Kit will be performed in all newly ascertained ALLFTD participants (n=1,600) and combined with previously obtained genotype data (n=1,100) to determine the ethnicity and relatedness between ALLFTD participants, to call copy-number variants (CNVs) and to calculate PGRS; 2) Perform targeted mutation analysis in ALLFTD participants. We will follow an efficient, step-wise, approach to genetically characterize ALLFTD participants, including C9orf72 and ATXN2 repeat expansion testing, targeted gene sequencing of ~300 neurodegenerative disease genes with sequence validation and manual curation of observed variants using American College of Medical Genetics and Genomics guidelines, and whole-genome sequencing and analysis of newly ascertained genetically unexplained familial FTLD patients; and 3) Generate PGRS for ALLFTD participants. Distinct datasets from published genome-wide association studies will be used to generate PGRS in study participants for use in the Projects, including PGRS for individual neurodegenerative diseases and PGRS that reflect related pathologies such as immunological disorders. As our sample size increases we will further derive PGRS from genomic data generated as part of ALLFTD, especially for FTLD clinical subtypes.

Researcher(s)

• Promoter: Rademakers Rosa

Research team(s)

• VIB CMN - Applied and Translational Neurogenomics

Project type(s)

• Research Project

Abstract

Research in our group is focused on the discovery and functional characterization of novel disease genes implicated in Frontotemporal dementia (FTD) and related disorders. Together our findings provide new insight into the pathomechanisms underlying FTD and contribute to the development of biomarkers and to the identification new targets for neurodegenerative disease therapies. While significant progress has been made in recent years, its diagnosis can be challenging and no treatments to slow or stop disease progression exist, highlighting the enormous unmet medical need of FTLD patients. Several genes including GRN and C9orf72 are associated with FTLD explaining less than 50% of the patient population. Importantly, even in patients with GRN and C9orf72 mutations, clinical research has demonstrated that the age at symptom onset and clinical phenotype is highly variable and disease penetrance incomplete, creating a significant challenge for counseling of FTLD patients and their asymptomatic relatives. In that context, we recently showed that genetic variants in and around the gene encoding transmembrane protein 106 B (TMEM106B) are able to modify disease onset and/or presentation in such patients. The overarching hypothesis is that insights derived from understanding the genetic basis of FTLD will lead to the elucidation of pathways underlying neurodegeneration. In order to obtain a comprehensive understanding of disease mechanisms, we need to generate multi-omics data including genetics, epigenetics and proteomics at the tissue and single cell levels. In our Research Program, we aim to identify and validate new candidate genes/pathways using large cohorts of patients and controls. In-depth functional characterization is subsequently performed in cellular models using state of the art technologies.

Researcher(s)

• Promoter: Rademakers Rosa

Research team(s)

• VIB CMN - Applied and Translational Neurogenomics

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Rademakers Rosa

Research team(s)

Project type(s)

• Research Project

Abstract

The Genetic Service Facility (GSF) is a central core facility in the VIB Department of Molecular Genetics that offers its researchers via a robotic platform different genetic analyses such as DNA/RNA extractions, DNA sequencing, SNP genotyping and genome-wide STR linkage analyses. Hereto, the GSF is equipped with 1 Biomek FX and 2 Biomek NX robot platforms (Beckman) for automatic pre- and post processing of samples, three 3730XL capillary sequencers (Applied Biosystems) for DNA sequencing and STR genotyping, a SEQUENOM platform for high-throughput mass array spectrometric SNP genotyping. More recently, the GSF has also acquired an ABI5500xl SOLiD for high-throughput next generation sequencing within divers applications. Also the isolation of DNA and RNA from various sources is centralized in the GSF using Magtration System8Lx and Magtration 12GCplus systems as well as the production of EBV transformed lymphoblast cell lines. With an optimized database system LIMS (Laboratory Information Management System) and the use of Electronic Lab Notebooks (ELN) in a Good Laboratory Practice (GLP) environment the majority of data processing is performed automatically and in optimal conditions. Because of the recognition by the University of Antwerp and the VIB of the GSF as a centralized core facility, their scientists can now make use of the genetic and genomic services at marginal cost.

Researcher(s)

• Promoter: Rademakers Rosa
• Promoter: Van Broeckhoven Christine
• Co-promoter: Del-Favero Jurgen
• Co-promoter: Strazisar Mojca

Research team(s)

• VIB CMN - Applied and Translational Neurogenomics

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Rademakers Rosa

Research team(s)

Project type(s)

• Research Project

Abstract

Frontotemporal dementia (FTD) is a degenerative condition of the anterior part of the brain that is clinically characterized by dramatic changes in personality, behavior and some thought processes. Neuropathologically, some FTD patients are characterized by neuronal and glial deposits of the microtubule associated protein tau (mapt) and in these patients, mutations in the MAPT gene are identified. However, not all patients show tau depositions in their brain and in this tau-negative type of FTD, no MAPT mutations were identified. By performing a genome-wide scan in a family segregating FTD characterized by tau-negative, ubiquitin-positive neuronal inclusions we identified a locus on chromosome 17q21. Fine mapping identified a candidate region of 4.8 centimorgans containing the MAPT gene. However, extensive mutation analysis of all exons and flanking intronic sequences of MAPT failed to identify a disease-related mutation. To date, 9 families are linked to chromosome 17q21 in the absence of MAPT mutations suggesting that this molecular genetic defect might be a common cause of FTD. We propose to perform further molecular genetic studies in patients of chromosome 17q21 linked tau negative FTD families to identify this genetic defect using 3 major strategies. First, we will determine the sequence of the complete MAPT gene in patients and a control individual to identify possible mutations in non-coding regions of MAPT, e.g. regulating its transcript levels or splice variant ratios. Second, we will analyze the genomic region of the MAPT gene for possible structural defects by fluorescent in situ hybridization experiments on DNA-fibers (fiber-FISH) of patients and healthy controls, complemented with pulsed-field gel electrophoresis experiments. Third, we will identify other positional candidate genes by in silico analyses of the genomic DNA sequence of the complete candidate region and we will perform mutation analyses of these candidate genes by sequence analyses of coding exons and flanking intronic sequences. Identifying this genetic will contribute to the understanding of chromosome 17 linked tau negative FTD and other, clinically overlapping, phenotypes.

Researcher(s)

• Promoter: Cruts Marc
• Co-promoter: Rademakers Rosa

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of this project is to identify the genetic defect responsible for tau-negative FTD at 17q21. It is expected that the identification of this genetic defect will greatly enhance our understanding of the biochemical processes involved in FTD pathology. Extensive molecular genetic analysis of MAPT, the most important candidate gene at 17q21, will also provide valuable information on FTD related tauopathies such as AD, PSP and CBD. The objectives of this project are: 1) Identifying the genetic defect responsible for chromosome 17-linked tau negative FTD, 2) Characterization of the genomic organization of the MAPT region with respect to the chromosome 17q21 low-copy repeats, 3) Constructing a complete SNP and haplotype map of the MAPT genomic region and Refining the genetic association of MAPT haplotype H1 in PSP and related tauopathies.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Fellow: Rademakers Rosa

Research team(s)

Project type(s)

• Research Project

Abstract

Gelieve aan te vullen a.u.b.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Fellow: Rademakers Rosa

Research team(s)

Project type(s)

• Research Project

Abstract

Alzheimer's disease (AD) is the most frequent form of senile dementia and the most common cause of death in western societies. AD is at least in part caused by genetic factors and in some cases AD segregates as a monogenic, autosomal dominant trait in families. In 18 to 50% of these monogenic cases, mutations have been identified in the ß-amyloid precursor protein gene (APP), the presenilin-1 (PSEN1) and the presenilin-2 (PSEN2) genes. The aim of this project is to identify new genes in which mutations are responsible for autosomal dominant AD using a positional cloning strategy.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Fellow: Rademakers Rosa

Research team(s)

Project type(s)

• Research Project

Abstract

Alzheimer's disease (AD) is the most frequent form of senile dementia and the most common cause of death in western societies. AD is at least in part caused by genetic factors and in some cases AD segregates as a monogenic, autosomal dominant trait in families. In 18 to 50% of these monogenic cases, mutations have been identified in the ß-amyloid precursor protein gene (APP), the presenilin-1 (PSEN1) and the presenilin-2 (PSEN2) genes. The aim of this project is to identify new genes in which mutations are responsible for autosomal dominant AD using a positional cloning strategy.

Researcher(s)

• Promoter: Van Broeckhoven Christine
• Fellow: Rademakers Rosa

Research team(s)

Project type(s)

• Research Project