A5000108065- Amyotrophic Lateral Sclerosis Research
- Neurogenetic and Muscular Disorders Research
- Cellular transport and secretion
- RNA Research and Splicing
- Neurological diseases and metabolism
- Endoplasmic Reticulum Stress and Disease
- RNA regulation and disease
- Parkinson's Disease Mechanisms and Treatments
- RNA and protein synthesis mechanisms
- Microtubule and mitosis dynamics
- Axon Guidance and Neuronal Signaling
- Receptor Mechanisms and Signaling
- Neuroscience and Neuropharmacology Research
- Cancer-related gene regulation
- Genetic Neurodegenerative Diseases
- Nuclear Structure and Function
- RNA modifications and cancer
- Biotin and Related Studies
- Genetics and Neurodevelopmental Disorders
- Mitochondrial Function and Pathology
- Kruppel-like factors research
- Regulation of Appetite and Obesity
- ATP Synthase and ATPases Research
- Ubiquitin and proteasome pathways
- Genomics and Rare Diseases
Vrije Universiteit Amsterdam
2024-2025
University Medical Center Utrecht
2009-2025
Utrecht University
2012-2024
University of Cambridge
2018-2019
Local translation regulates the axonal proteome, playing an important role in neuronal wiring and axon maintenance. How mRNAs are localized to specific subcellular sites for translation, however, is not understood. Here we report that RNA granules associate with endosomes along axons of retinal ganglion cells. RNA-bearing Rab7a late also ribosomes, real-time imaging reveals they local protein synthesis. We show often pause on mitochondria encoding proteins mitochondrial function translated...
Objective How hexanucleotide (GGGGCC) repeat expansions in C9ORF72 cause amyotrophic lateral sclerosis (ALS) remains poorly understood. Both gain‐ and loss‐of‐function mechanisms have been proposed. Evidence supporting these vivo is, however, incomplete. Here we determined the effect of C9orf72 mice. Methods We generated analyzed a conditional knockout mouse model. fl/fl mice were crossed with Nestin‐Cre to selectively remove from neurons glial cells. Immunohistochemistry was performed study...
Mutations in the RNA binding protein fused sarcoma/translated liposarcoma (FUS/TLS) cause amyotrophic lateral sclerosis (ALS). Although ALS-linked mutations FUS often lead to a cytosolic mislocalization of protein, pathogenic mechanisms underlying these remain poorly understood. To gain insight into mechanisms, we examined biochemical, cell biological and functional properties mutant neurons. Expression different mutants (R521C, R521H, P525L) neurons caused axonal defects. A interaction...
Ribosome assembly occurs mainly in the nucleolus, yet recent studies have revealed robust enrichment and translation of mRNAs encoding many ribosomal proteins (RPs) axons, far away from neuronal cell bodies. Here, we report a physical functional interaction between locally synthesized RPs ribosomes axon. We show that axonal RP is regulated through sequence motif, CUIC, forms an RNA-loop structure region immediately upstream initiation codon. Using imaging subcellular proteomics techniques,...
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment available. An increasing number of genetic causes ALS are being identified, but how these defects lead to motor neuron degeneration and which extent they affect common cellular pathways remains incompletely understood. To address questions, we performed an interactomic analysis identify binding partners wild-type (WT) ALS-associated mutant versions ATXN2, C9orf72, FUS, OPTN, TDP-43 UBQLN2 in...
Local mRNA translation in axons is critical for the spatiotemporal regulation of axonal proteome. A wide variety mRNAs are localized and translated axons; however, how protein synthesis regulated at specific subcellular sites remains unclear. Here, we establish that endoplasmic reticulum (ER) supports developing rat hippocampal cultured neurons. Axonal ER tubule disruption impairs local ribosome distribution. Using nanoscale resolution imaging, find ribosomes make frequent contacts with...
Extrinsic cues trigger the local translation of specific mRNAs in growing axons via cell surface receptors. The coupling ribosomes to receptors has been proposed as a mechanism linking signals but it is not known how broadly this operates, nor whether can selectively regulate mRNA translation. We report that receptor-ribosome employed by multiple guidance cue and interaction mRNA-dependent. find different associate with distinct sets RNA-binding proteins. Cue stimulation
Abstract Neuronal function relies on careful coordination of organelle organization and transport. Kinesin-1 mediates transport the endoplasmic reticulum (ER) lysosomes into axon it is increasingly recognized that contacts between ER influence organization. However, unclear how organization, inter-organelle communication are linked this contributes to local availability in neurons. Here, we show somatic tubules required for proper lysosome axon. Somatic tubule disruption causes accumulation...
Previously, we have reported amyotrophic lateral sclerosis (ALS) families with multiple mutations in major ALS-associated genes. These findings provided evidence for an oligogenic basis of ALS. In our present study, screened a cohort 755 sporadic ALS patients, 111 familial patients (97 families), and 765 control subjects Dutch descent vesicle-associated membrane protein B (VAPB). We identified 1 novel VAPB mutation (p.V234I) patient known to chromosome 9 open reading frame 72 (C9orf72)...
Abstract Adoptive cell-based therapy utilizing chimeric antigen receptor (CAR)-T technology holds promise in the field of neuro-oncology. Significant progress has been made enhancing both efficacy and safety CAR-T cell therapies. However, challenges such as multifaceted immunosuppressive impact tumour microenvironment (TME) insufficient infiltration into brain sites remain a major hurdle. Emerging novel approaches CAR-macrophages (CAR-MACs) show potent results for immunotherapy. CAR-MACs...
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase susceptibility. In contrast, rare copy-number (CNVs), been associated with neuropsychiatric traits, not studied for ALS well-powered study populations. To examine role of CNVs susceptibility, we conducted CNV including over 19 000 individuals. screen 1875...
Mutations in NIPA1 cause Hereditary Spastic Paraplegia type 6, a neurodegenerative disease characterized by an (upper) motor neuron phenotype. Deletions of have been associated with higher susceptibility to amyotrophic lateral sclerosis (ALS). The exact role genetic variation ALS and course is, however, not known. We sequenced the entire coding sequence genotyped polyalanine repeat located first exon NIPA1. A total 2292 patients 2777 controls from three independent European populations were...
In the past decade, a growing amount of evidence has demonstrated that organelles do not act autonomously and independently but rather communicate with each other to coordinate different processes for proper cellular function. With highly extended network throughout cell, endoplasmic reticulum (ER) plays central role in interorganelle communication through membrane contact sites. Here, we highlight recent indicating ER also forms contacts membrane-less organelles. These interactions...