applied and translational neurogenomics of ftld and

SCIENCE MEETS LIFE

Applied and Translational Neurogenomics of FTLD and related disorders Group Leader: Prof. Dr. Rosa Rademakers (rosa.rademakers@uantwerpen.vib.be)

Group Members: Dr. Cyril Pottier – Staff scientist (cyril.pottier@uantwerpen.vib.be) Dr. Cristina Vicente – Postdoc (cristina.vicente@uantwerpen.vib.be)Dr. Wouter De Coster – Postdoc (wouter.decoster@uantwerpen.vib.be)

• Interest in an interdisciplinary applied research project

• Strong interest in Genetics and Bioinformatics

• Proficient in English• Team player

FTLD pathology is also diverse: A) Tau staining of an FTLD-taupatient’s cortex with corticobasal degeneration. B) TDP-43 stainingof an FTLD-TDP patient’s cortical layer II. C) FUS staining of an FTLDpatient’s neocortex with ubiquitin-positive inclusions.

Clinical heterogeneity of FTLD patients

Pathological heterogeneity of FTLD-TDP patients

25.5%

13.9%57.7%

1.5%1.4%

Genetics of FTLD-TDP:While several importantFTLD genes have beenidentified, the geneticetiology of more than50% of patients remainsunexplained.

Genetic heterogeneity of FTLD-TDP patients

GENETIC MODIFIERS and DISEASE MODELS FUNCTIONAL FOLLOW-UP and MULTI-OMICs

C9orf72GRNTBK1OtherUnknown

The Rademakers lab leads international consortia to bringtogether clinical/pathological information and DNA/tissue samplesfrom FTLD patients and controls for research studies.

International FTLD Whole Genome Sequencing Consortium

NEW GENE DISCOVERY

EPIGENOME

TRANSCRIPTOMEGENOME

PROTEOME

BULK

SINGLECELL

Multi-OMICS Integration Signatures Therapeutics

Through our international consortia, we have established the largest collection ofhighly characterized and pathologically confirmed patients with FTLD, placing usas the leader in the FTLD genetics field.In order to identify patient specific signatures and potential therapeutic targets,we have and will continue to generate a wealth of genomics, transcriptomics,proteomics and epigenomics data.As some brain regions and cell types appear to be more affected than others, weplan to generate single cell multi-omics data to assess cell-type differences in thedisease etiology.To further dissect disease mechanisms, we use cellular models from patients andmouse models of disease.

OVERVIEW OF SCIENTIFIC APPROACHES

Whole genome sequencingWe employ several cutting edge technologies to unravelunderlying genetic risk for FTLD, including short and long readwhole genome sequencing. We recently identified DPP6, HLA andUNC13A as new candidate loci associated with disease risk.

Transcriptome and Proteome

Microarray approachWe use innovative approaches to identify genetic modifiers ofclinical presentation, for example by performing a genome-wideassociation study on GRN mutation carriers, identifyingTMEM106B and GFRA2 as genetic modifiers of diseasepresentation.

• In depth exploration of newly identified risk loci for FTLD and related diseases• Integration of multi-omics layers for gene discovery using computational methods• Establishment of cellular and organoid models • Single-cell multi-omics datasets on genetically unexplained and explained FTLD

patients

Functional follow-up

Reduced Representation Bisulfide Sequencing

We have generated a large DNA methylation dataset and areestablishing a workflow to generate single-cell datasets to studygenome-wide chromatin accessibility and histone modifications.

We study the effect of GWAS hits on both gene and protein levelsusing qPCR and Western blot. Additionally, we use in-vitromethods to investigate causal variants within the non-codinggenome such as luciferase assays and EMSA using diseaserelevant cell lines. We are now exploring the potential use of newmodels for high throughput studies, such as iPSCs and brainorganoids.

Epigenomics approaches

Proteomics

RNA-sequencing

ON-GOING AND FUTURE DIRECTIONS

Mouse modelsWe developed mouse models, such as knock-out mice for theTMEM106B protective gene. When crossed with transgenic micemodelling FTLD-C9orf72 or FTLD-Grn we reported increasedastrogliosis and no disease protection as initially anticipated.

A B C • Identify new causal/risk genes

• Discover disease modifiers

• Explore disease mechanisms

• Pinpoint new biomarkers and therapeutic targets

Dickson et al., 2019, Acta Neuropathol Commun

Pottier et al., 2019, Acta Neuropathol Pottier et al., 2018, Lancet Neurol

Nicholson et al., 2018, Acta Neuropathol Comm

YOUR PROFILE

The Rademakers’ lab is working on Frontotemporal lobardegeneration (FTLD) and related disorders. FTLD covers aspectrum of diseases with clinical presentations that includebehavioral, language, memory and movement dysfunctions.Many patients have a disease onset before 65 years.

OUR OFFER• Access to the largest cohort of FTLD

patients and controls biosamples• Multidisciplinary team• Large scientific network• Scientific excellence• International diversity

FTD-MND

Amyotrophic Lateral Sclerosis

Semanticvariant PPA

Non-fluentvariant PPA

Logopenicvariant PPA

Corticobasalsyndrome

Progressive Supranuclear Palsy

Behavioralvariant FTD

Cognitive lossMotor symptomsUpper and/or lowermotorneuronpathways

Cognitive lossBehaviorimpairmentMotor symptoms

Cognitive lossDisinhibitionInflexibilityDecrease insight

Fluent speechDecrease wordComprehensionandrecognition

Halting speechShort phrasesGrammar errors

Low speech outputWord retrieval problems

Cognitive andmemory lossAsymmetric rigidityApraxia

Behavioral andcognitive lossParkinsonismEye movement disturbances

hiPSC

Tau TDP-43 FUS

ATAC-Seq

Histone modification ChIP-seq

Human fibroblasts hiPSC Brain

organoidDifferentiated

cellsCRISPR

In our group, we have generated large datasets to investigateprotein and gene expression changes that correlate with diseasestatus. We reported that genes affecting vesicular transport maymodify the phenotype of C9orf72-linked diseases.