Author
Philip Van Damme
Other affiliations: Sunnybrook Health Sciences Centre, Public Health Research Institute, The Catholic University of America ...read more
Bio: Philip Van Damme is an academic researcher from Katholieke Universiteit Leuven. The author has contributed to research in topics: Amyotrophic lateral sclerosis & Medicine. The author has an hindex of 60, co-authored 247 publications receiving 11702 citations. Previous affiliations of Philip Van Damme include Sunnybrook Health Sciences Centre & Public Health Research Institute.
Papers published on a yearly basis
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Umeå University1, University of Edinburgh2, University Hospital of Lausanne3, University of Turin4, Katholieke Universiteit Leuven5, Beaumont Hospital6, Hochschule Hannover7, Queen Elizabeth Hospital Birmingham8, University of Milan9, Jagiellonian University Medical College10, Ludwig Maximilian University of Munich11, University Hospital of Basel12
TL;DR: The evidence base for the diagnosis and management of amyotrophic lateral sclerosis (ALS) is weak and needs to be strengthened, according to the authors.
Abstract: Background: The evidence base for the diagnosis and management of amyotrophic lateral sclerosis (ALS) is weak. Objectives: To provide evidence-based or expert recommendations for the diagnosis and ...
874 citations
TL;DR: It is shown that intracerebroventricular delivery of Vegf in a SOD1G93A rat model of ALS delays onset of paralysis, improves motor performance and prolongs survival by 22 d, representing the largest effects in animal models of ALS achieved by protein delivery.
Abstract: Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS
529 citations
Wouter van Rheenen1, Aleksey Shatunov2, Annelot M. Dekker1, Russell L. McLaughlin3 +184 more•Institutions (54)
TL;DR: Evidence of ALS being a complex genetic trait with a polygenic architecture is established and the SNP-based heritability is estimated at 8.5%, with a distinct and important role for low-frequency variants (frequency 1–10%).
Abstract: To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.
466 citations
TL;DR: Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia and Charcot-Marie-Tooth type 2.
444 citations
TL;DR: An increase of α-tubulin acetylation induced by pharmacological inhibition of histone deacetylase 6 (HDAC6) corrected the axonal transport defects caused by HSPB1 mutations and rescued the CMT phenotype of symptomatic mutant H SPB1 mice.
Abstract: Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. Mutations in the 27-kDa small heat-shock protein gene (HSPB1) cause axonal CMT or distal hereditary motor neuropathy (distal HMN). We developed and characterized transgenic mice expressing two different HSPB1 mutations (S135F and P182L) in neurons only. These mice showed all features of CMT or distal HMN dependent on the mutation. Expression of mutant HSPB1 decreased acetylated α-tubulin abundance and induced severe axonal transport deficits. An increase of α-tubulin acetylation induced by pharmacological inhibition of histone deacetylase 6 (HDAC6) corrected the axonal transport defects caused by HSPB1 mutations and rescued the CMT phenotype of symptomatic mutant HSPB1 mice. Our findings demonstrate the pathogenic role of α-tubulin deacetylation in mutant HSPB1-induced neuropathies and offer perspectives for using HDAC6 inhibitors as a therapeutic strategy for hereditary axonopathies.
431 citations
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TL;DR: It is found that repeat expansion in C9ORF72 is a major cause of both FTD and ALS, suggesting multiple disease mechanisms.
4,153 citations
National Institutes of Health1, Cardiff University2, VU University Amsterdam3, Erasmus University Rotterdam4, University of Manchester5, University College London6, University of Helsinki7, University of Oulu8, Georgetown University9, Johns Hopkins University10, Illumina11, University Hospital of Wales12, University of Eastern Finland13, University of Miami14, University of Turin15, University of Cagliari16, The Catholic University of America17, Microsoft18, University of Toronto19, University of Würzburg20, University of Washington21, Aneurin Bevan University Health Board22
TL;DR: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases, and a large hexanucleotide repeat expansion in the first intron of C9ORF72 is shown.
3,784 citations
TL;DR: These findings support developments of new therapeutic approaches for chronic neurodegenerative disorders directed at the blood-brain barrier and other nonneuronal cells of the neurovascular unit.
2,797 citations
TL;DR: The remarkable range of discoveriesGWASs has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics are reviewed.
Abstract: Application of the experimental design of genome-wide association studies (GWASs) is now 10 years old (young), and here we review the remarkable range of discoveries it has facilitated in population and complex-trait genetics, the biology of diseases, and translation toward new therapeutics. We predict the likely discoveries in the next 10 years, when GWASs will be based on millions of samples with array data imputed to a large fully sequenced reference panel and on hundreds of thousands of samples with whole-genome sequencing data.
2,669 citations
TL;DR: Mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer's disease, are examined, and therapeutic opportunities relating to these neurovascular deficits are highlighted.
Abstract: The neurovascular unit (NVU) comprises brain endothelial cells, pericytes or vascular smooth muscle cells, glia and neurons. The NVU controls blood-brain barrier (BBB) permeability and cerebral blood flow, and maintains the chemical composition of the neuronal 'milieu', which is required for proper functioning of neuronal circuits. Recent evidence indicates that BBB dysfunction is associated with the accumulation of several vasculotoxic and neurotoxic molecules within brain parenchyma, a reduction in cerebral blood flow, and hypoxia. Together, these vascular-derived insults might initiate and/or contribute to neuronal degeneration. This article examines mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer's disease, and highlights therapeutic opportunities relating to these neurovascular deficits.
2,256 citations