A5039056825- Amyotrophic Lateral Sclerosis Research
- Parkinson's Disease Mechanisms and Treatments
- Alzheimer's disease research and treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Neurological diseases and metabolism
- Single-cell and spatial transcriptomics
- Lysosomal Storage Disorders Research
- Neurological Disease Mechanisms and Treatments
- MicroRNA in disease regulation
- Dementia and Cognitive Impairment Research
- Immune cells in cancer
- Neurogenesis and neuroplasticity mechanisms
- Genetics and Neurodevelopmental Disorders
- Epigenetics and DNA Methylation
- Immune Cell Function and Interaction
- Animal Genetics and Reproduction
- RNA Research and Splicing
- Neurogenetic and Muscular Disorders Research
- Bioinformatics and Genomic Networks
- Inflammation biomarkers and pathways
- Mitochondrial Function and Pathology
- T-cell and Retrovirus Studies
- Amino Acid Enzymes and Metabolism
- Metabolism and Genetic Disorders
- Connective tissue disorders research
Indiana University – Purdue University Indianapolis
2020-2024
Indiana University School of Medicine
2020-2024
Neurosciences Institute
2023
University of Indianapolis
2023
VIB-UAntwerp Center for Molecular Neurology
2011-2021
Indiana University
2020-2021
University of Antwerp
2011-2018
KU Leuven
2015
ZNA Middelheim Hospital
2015
University Medical Center Groningen
2015
<h3>Objective:</h3> To assess the genetic contribution of <i>TBK1</i>, a gene implicated in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and FTD-ALS, Belgian FTD ALS patient cohorts containing significant part genetically unresolved patients. <h3>Methods:</h3> We sequenced <i>TBK1</i> hospital-based cohort 482 unrelated patients with FTD-ALS 147 an extended family DR158. followed up mutation carriers by segregation studies, transcript protein expression analysis,...
To characterize patients with frontotemporal lobar degeneration (FTLD) a repeat expansion mutation in the gene C9orf72, and to determine whether there are differences clinical presentation compared FTLD carriers of GRN or MAPT without mutation.Patient series.Dementia clinics Flanders, Belgium.Two hundred seventy-five genetically phenotypically thoroughly characterized FTLD.Clinical demographic characteristics 26 C9orf72 mutation, as well familial sporadic mutation.C9orf72 developed at an...
SPI1 was recently reported as a genetic risk factor for Alzheimer's disease (AD) in large-scale genome-wide association studies. However, it is unknown whether should be downregulated or increased to have therapeutic benefits. To investigate the effect of modulating levels on AD pathogenesis, we performed extensive biochemical, histological, and transcriptomic analyses using both Spi1-knockdown Spi1-overexpression mouse models. Here, show that knockdown Spi1 expression significantly...
Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) are clinically, pathologically etiologically disorders embedded in the body (LBD) continuum, characterized by neuronal α-synuclein pathology. Rare homozygous compound heterozygous premature termination codon (PTC) mutations Vacuolar Protein Sorting 13 homolog C gene (VPS13C) associated early-onset recessive PD. We observed two siblings age (< 45) autopsy confirmed DLB, missense VPS13C, p.Trp395Cys p.Ala444Pro, inherited from their...
We investigated the genetic role of sortilin (SORT1) in frontotemporal dementia (FTD). SORT1 is neuronal receptor for granulin, encoded by progranulin gene (GRN), a major causal inherited FTD. In Belgian cohorts 636 FTD patients and 1066 unaffected control individuals, we identified 5 patient-only nonsynonymous rare variants SORT1. Rare variant burden analysis showed significant increase coding compared to individuals (p = 0.04), particularly β-propeller domain with 2 located predicted...
Abstract INTRODUCTION Rare variants in ABCA1 increase the risk of developing Alzheimer's disease (AD). facilitates lipidation apolipoprotein E (apoE). This study investigated whether microRNA‐33 (miR‐33)‐mediated regulation this ABCA1–APOE pathway affects phenotypes an amyloid mouse model. METHODS We generated mir‐33 +/+ ; APP/PS1 and −/− mice to determine changes pathology using biochemical histological analyses. used RNA sequencing mass spectrometry identify transcriptomic proteomic...
We previously reported a granulin (GRN) null mutation, originating from common founder, in multiple Belgian families with frontotemporal dementia. Here, we used data of 10-year follow-up study to describe detail the clinical heterogeneity observed this extended founder pedigree. identified 85 patients and 40 unaffected mutation carriers, belonging 29 branches Most (74.4%) were diagnosed dementia, while others had diagnosis unspecified Alzheimer's dementia or Parkinson's disease. The can...
TAR DNA-binding protein 43 (TDP-43) inclusions are pathological hallmarks of patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Loss TDP-43 in zebrafish engenders a severe muscle vascular phenotype concomitant elevation filamin C (FLNC) levels, an observation confirmed the frontal cortex FTLD-TDP patients. Here, we aimed to further assess contribution FLNC dementia (FTD) etiology. We conducted mutational screening cohort 529 unrelated Belgian FTD...
Summary Astrocytes are the most common glial cell type in brain, yet, it is unclear how their activation affects transcriptome of neighboring cells. Engineered G protein-coupled receptors (GPCRs) called Designer Receptors Exclusively Activated by Drugs (DREADDs) enable selective specific types, such as astrocytes. Here, we combine astrocytes hippocampus and cortex healthy mice with single-cell RNA sequencing. Our data show that long-term dramatically alters microglia. Genes were...
Previous research demonstrated that genetic heterogeneity is a critical factor in modeling amyloid accumulation and other Alzheimer’s disease phenotypes. However, it unknown what mechanisms underlie these effects of background on tau aggregate-driven pathogenicity. In this study, we induced aggregation wild-derived mice by expressing MAPT. To investigate the effect action aggregates, performed RNA sequencing with brains C57BL/6J, CAST/EiJ, PWK/PhJ, WSB/EiJ (n = 64) determined core...
Abstract Background microRNAs have emerged as a new class of therapeutic targets that regulate the expression target genes by binding their 3’‐untranslated regions. Growing evidence suggests dysregulation may contribute to onset and/or progression various diseases. However, functional and implications microRNA in Alzheimer’s disease (AD) remain largely unclear. To gain insight into roles AD pathogenesis, we recently performed unbiased profiling with entorhinal cortices age‐matched...
Abstract Although there have been numerous expression quantitative trait loci (eQTL) studies, the effect of genetic variants on levels multiple plasma proteins still warrants more systematic investigation. To identify modifiers that influence clinically relevant proteins, we performed protein locus (pQTL) mapping 92 using Diversity Outbred (DO) mouse population and identified 12 significant cis 6 trans pQTL. Among them, discovered coding in a -pQTL Ahr trans- pQTL Rfx1 for IL-17A protein....
Mouse genetic backgrounds have been shown to modulate amyloid accumulation and propagation of tau aggregates. Previous research into these effects has highlighted the importance studying impact heterogeneity on modeling Alzheimer's disease. However, it is unknown what mechanisms underly background disease, specifically aggregate-driven pathogenicity. In this study, we induced aggregation in wild-derived mice by expressing MAPT (P301L). To investigate effect action aggregates, performed RNA...
Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are two extremes of the same disease spectrum. Most notable genetic evidence for this link came from recent identification G 4 C 2 repeat expansions in promoter C9orf72 as most common cause ALS together with GRN MAPT third major gene FTLD. Moreover, FTLD-ALS is first causal explaining part familial FTLD-ALS. In brain, expression was significantly reduced by 50%. Different possible mechanisms were proposed...
Describe in-depth the clinical and pathological characteristics of patients belonging to Belgian GRN founder family consisting 29 branches. Investigate effect known genetic risk variants on disease onset age.
Abstract Background Dementia with Lewy bodies (DLB) and Parkinson’s disease (PD) are clinically, pathologically etiologically overlapping disorders. They included in the body (LBD) continuum characterized by α-synuclein-positive pathology neurons. Homozygous PTC mutations Vacuolar Protein Sorting 13 homolog C gene ( VPS13C ) associated early-onset PD. Methods Whole genome sequencing of two affected siblings healthy parents family A onset age below 50 years DLB confirmed at autopsy. Targeted...