Cell Biology, Faculty of Science, Utrecht University
Prof. dr. C.C. Hoogenraad
0031 (0)30 2534585
Despite the progress in our understanding of neurological and psychiatric diseases, there are still no disease-modifying therapeutics. The discrepancy between the number of lead compounds and approved drugs may partially be a result of the methods used to generate the leads and highlights the need for new technology to obtain more detailed and physiologically relevant information on neurobiological processes in normal and diseased states. Primary neuronal cells represent a unique model for addressing fundamental questions in neurobiology – the size, shape and specialized functions of primary cultured neurons permit analyses of neuronal migration, axon and dendrite polarity, and synapse formation and function. Moreover, the culture models represent a unique system to understand neurological and psychiatric disease mechanisms and identify therapeutics. Our laboratory established primary neurons (from rat and mouse), brain slices (from rat and mouse) and neurons derived from human induced pluripotent stem (iPS) cells of a variety of neurological diseases, including Huntington’s disease (HD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS), with the aim of using these models to understand disease mechanisms and identify therapeutics. We combined the primary neuron models, automated microscopy (Nikon-biostation), and automatic phenotype analysis (such as cell dead) into a neuron screening workflow to create a platform that can be used for drug screening, drug testing, and small-scale protein or genetic screens and RNAi screens. This screening platform can also be applied to primary cell models of other non-neuronal diseases.
- Biomedical & health
- Primary neuron model systems ('biological system')
- Automated microscopy ('bioimaging')
- Automatic phenotype analysis ('phenotyping')
- Neurobiology research
- Biology and chemistry
- Disease biology
- Translational neuroscience
Expertise and Track Record
435002024 Biomarker selection and validation for retinal imaging of neurodegenerative diseases With Amelink (TNO).
The combination of IPs cells, primary neuron model systems (‘biological system’), automated microscopy (‘bioimaging’), and automatic phenotype analysis (‘phenotyping’) is a unique screening platform in the Netherlands. The develop of new disease-specific iPS cells and optimize the neuron-screening platform for new disease-specific phenotypes will be give us a front row seat in our understanding of disease mechanisms and identifying new therapeutics. The proposed screening platform provides a unique in vitro system for preclinical drug discovery, neurotoxicity testing, predictive disease modelling, and basic cellular research.
Three typical projects that my lab has recently supported:
1. Benoit RM, Frey D, Hilbert M, Kevenaar JT, Wieser MM, Stirnimann CU, McMillan D, Ceska T, Lebon F, Jaussi R, Steinmetz MO, Schertler GF, Hoogenraad CC, Capitani G, Kammerer RA (2014) Structural basis for recognition of synaptic vesicle protein 2C by botulinum neurotoxin A.. Nature. 505(7481):108-11
2. Hellal F, Hurtado A, Ruschel J, Flynn KC, Laskowski CJ, Umlauf M, Kapitein LC, Strikis D, Lemmon V, Bixby J, Hoogenraad CC, Bradke F (2011) Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury. Science 331(6019):928-31
3. Stiess M, Maghelli N, Kapitein LC, Gomis-Rüth S, Wilsch-Bräuninger M, Hoogenraad CC, Tolic Nørrelykke IM, Bradke F. (2010) Axon extension occurs independently of centrosomal microtubule nucleation. Science 327(5966):704-7
- van Spronsen M, Mikhaylova M, Lipka J, Schlager MA, van den Heuvel DJ, Kuijpers M, Wulf PS, Keijzer N, Demmers J, Kapitein LC, Jaarsma D, Gerritsen HC, Akhmanova A and Hoogenraad CC (2013) TRAK/Milton Motor-Adaptor Proteins Steer Mitochondrial Trafficking to Axons and Dendrites, Neuron. 77(3):485-502 [IF:14.7]
- Hellal F, Hurtado A, Ruschel J, Flynn KC, Laskowski CJ, Umlauf M, Kapitein LC, Strikis D, Lemmon V, Bixby J, Hoogenraad CC, Bradke F (2011) Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury. Science 331(6019):928-31 [IF:29.7]
- Stiess M, Maghelli N, Kapitein LC, Gomis-Rüth S, Wilsch-Bräuninger M, Hoogenraad CC, Tolic Nørrelykke IM, Bradke F. (2010) Axon extension occurs independently of centrosomal microtubule nucleation. Science 327(5966):704-7 [IF:28,1]
- Kapitein LC, Schlager MA, Kuijpers M, Wulf PS, van Spronsen M, MacKintosh FC, Hoogenraad CC (2010). Mixed microtubules steer dynein-driven cargo transport into dendrites. Current Biol 20(4):290-299 [IF:10.8] (selected as a "must read" by Faculty of 1000)
- Jaworski J, Kapitein LC, Montenegro Gouveia S, Dortland BR, Wulf PS, Grigoriev I, Camera P, Spangler SA, Di Stefano P, Demmers J, Krugers H, Defilippi P, Akhmanova A, Hoogenraad CC. (2009) Dynamic microtubules regulate dendritic spine morphology and synaptic plasticity. Neuron, 61(1), 85-100 [IF:13.4] (Preview by P. Penzes et al.,) (selected as a "Exceptional" by Faculty of 1000)
In 2012, de Stichting voor Fundamenteel Onderzoek der Materie (FOM) awarded us a FOM programme named ‘Barriers in the brain: the molecular physics of learning and memory’, which is part of Topsector Life Sciences and Health. A team of five scientists from different Dutch Institutes are part of this programma; Dr.ir. Erwin J.G. Peterman (program leader, VU); Prof.dr. Casper C. Hoogenraad (project-leader, UU), Prof.dr. Thomas Schmidt (project-leader, LU), Dr. Lukas C. Kapitein (project-leader, UU), Dr. Cornelis Storm (project-leader, TUE). The programme focuses on the molecular physical processes underlying regulation of synaptic strength, with special emphasis on spines: the transmitting end of synapses. By using an interdisciplinary approach, ranging from single-molecule biophysics in vitro and in vivo, via soft-matter theory, to neuronal cell biology, we seek to quantify the basic, physical processes that are at the heart of synaptic strength-regulation.
- dedicated postdocs: 1 fte
- dedicated technicians: 2 fte
- Confocal Zeiss LSM 700
- Confocal Zeiss LSM 700-2
- Confocal Zeiss LSM 5 Pascal
- Spinning Disc Nikon-Roper ILAS PhotoAblation
- TIRF Nikon-Roper ILAS
- Tissue culture lab, Molecular Biology lab