Dr. L.P. (Lars) van der Heide
- Science Park 904
- Room number: C3.104
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Postbus 94246
1090 GE Amsterdam
- Macrobian-Biotech
- www.macrobianbiotech.com
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Research
1) The BCL2 code to dopaminergic development and Parkinson's disease
Currently, there is no real cure for Parkinson's disease (PD), the second most common neurodegenerative disorder. Attenuating the rate of cell death would obviously be beneficial for PD patients, and key to understanding why dopaminergic neurons in the Substantia Nigra compacta (SNc) degenerate is understanding the genetic makeup that causes this predisposition. The answer may lie in the embryonic development of dopaminergic neurons in the SNc, which is coordinated by a multitude of both transcription and growth factors. This developmental program generates such a diversity that one could say that every adult neuron has its own identity and one cannot substitute for another. However, a major common denominator of developing dopaminergic neurons is that they undergo cell death when key transcription factors or growth factors are absent. We propose that these key transcription factors and growth factors control the expression of BCL2 proteins, proteins which directly control the balance between neuronal survival and death. By hijacking the BCL2 system controlling neuronal survival and death, neurodegeneration in PD may be therapeutically prevented and is the penultimate goal of this study.
By using a Parkinson's disease mouse model and state of the art techniques we will identify the BCL2 factors expressed in dopaminergic neurons of the SNc and examine their individual contribution to neuronal survival. By manipulating the levels of the identified BCL2 factors and their upstream regulators we will identify novel targets to enhance dopaminergic viability which may serve as novel candidates for therapeutic intervention.
BCL2 balance in dopaminergic development and Parkinson's disease (adapted from van der Heide and Smidt TMM 2013) van der Heide Lab -
Master Molecular Neurosciences
Molecular Neurosciences is part of the Master's programme Neurobiology.
A basic understanding of molecular principles is the key for developing novel treatment paradigms for psychiatric and neurological diseases such as schizophrenia and Parkinson’s. The Master’s track in Molecular Neurosciences provides a training platform for students who have the ambition to play a major role in looking for solutions for the diseases of today and tomorrow.
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Publications
2023
Stoop, J., Douma, E. H., van der Vlag, M., Smidt, M. P., & van der Heide, L. P. (2023). Tyrosine hydroxylase phosphorylation is under the control of serine 40. Journal of neurochemistry, 167(3), 376-393. https://doi.org/10.1111/jnc.15963 [details]
2022
- Robinson, E. J., Aguiar, S. P., Kouwenhoven, W. M., Starmans, D. S., von Oerthel, L., Smidt, M. P., & van der Heide, L. P. (2022). Correction to: Survival of midbrain dopamine neurons depends on the Bcl2 factor Mcl1. Cell death discovery, 8, Article 102. https://doi.org/10.1038/s41420-022-00871-3
2021
- van de Vis, R. A. J., Moustakas, A., & van der Heide, L. P. (2021). NUAK1 and NUAK2 Fine-Tune TGF-β Signaling. Cancers, 13(13), Article 3377. https://doi.org/10.3390/cancers13133377 [details]
2019
- Kolliopoulos, C., Raja, E., Razmara, M., Heldin, P., Heldin, C-H., Moustakas, A., & van der Heide, L. P. (2019). Transforming growth factor β (TGFβ) induces NUAK kinase expression to fine-tune its signaling output. The Journal of Biological Chemistry, 294(11), 4119-4136. https://doi.org/10.1074/jbc.RA118.004984 [details]
- Robinson, E. J., Aguiar, S., Smidt, M. P., & van der Heide, L. P. (2019). MCL1 as a Therapeutic Target in Parkinson's Disease? Trends in Molecular Medicine, 25(12), 1056-1065. https://doi.org/10.1016/j.molmed.2019.08.009 [details]
2018
- Robinson, E. J., Aguiar, S. P., Kouwenhoven, W. M., Starmans, D. S., von Oerthel, L., Smidt, M. P., & van der Heide, L. P. (2018). Survival of midbrain dopamine neurons depends on the Bcl2 factor Mcl1. Cell death discovery, 4, Article 107. https://doi.org/10.1038/s41420-018-0125-7 [details]
2016
- Kouwenhoven, W. M., Veenvliet, J. V., van Hooft, J. A., van der Heide, L. P., & Smidt, M. P. (2016). Engrailed 1 shapes the dopaminergic and serotonergic landscape through proper isthmic organizer maintenance and function. Biology Open, 5(3), 279-288. https://doi.org/10.1242/bio.015032 [details]
2015
- van der Heide, L. P., Wijchers, P. J. E. C., von Oerthel, L., Burbach, J. P. H., Hoekman, M. F. M., & Smidt, M. P. (2015). FoxK2 is required for cellular proliferation and survival. Journal of Cellular Physiology, 230(5), 1013-1023. https://doi.org/10.1002/jcp.24828 [details]
2014
- Dahl, M., Maturi, V., Lönn, P., Papoutsoglou, P., Zieba, A., Vanlandewijck, M., van der Heide, L. P., Watanabe, Y., Söderberg, O., Hottiger, M. O., Heldin, C-H., & Moustakas, A. (2014). Fine-tuning of Smad protein function by poly(ADP-ribose) polymerases and poly(ADP-ribose) glycohydrolase during transforming growth factor β signaling. PLoS ONE, 9(8), e103651. https://doi.org/10.1371/journal.pone.0103651
2013
- Hoekstra, E. J., von Oerthel, L., van der Heide, L. P., Kouwenhoven, W. M., Veenvliet, J. V., Wever, I., Jin, Y. R., Yoon, J. K., van der Linden, A. J. A., Holstege, F. C. P., Groot Koerkamp, M. J., & Smidt, M. P. (2013). Lmx1a Encodes a Rostral Set of Mesodiencephalic Dopaminergic Neurons Marked by the Wnt/B-Catenin Signaling Activator R-spondin 2. PLoS ONE, 8(9), Article e74049. https://doi.org/10.1371/journal.pone.0074049 [details]
- Hoekstra, E. J., von Oerthel, L., van der Linden, A. J. A., Schellevis, R. D., Scheppink, G., Holstege, F. C. P., Groot-Koerkamp, M. J., van der Heide, L. P., & Smidt, M. P. (2013). Lmx1a is an activator of Rgs4 and Gbr10 and is responsible for the correct specification of rostral and medial mdDA neurons. European Journal of Neuroscience, 37(1), 23-32. Advance online publication. https://doi.org/10.1111/ejn.12022 [details]
- van der Heide, L. P., & Smidt, M. P. (2013). The BCL2 code to dopaminergic development and Parkinson's disease. Trends in Molecular Medicine, 19(4), 211-216. https://doi.org/10.1016/j.molmed.2013.02.003 [details]
2011
- van der Heide, L. P., van Dinther, M., Moustakas, A., & ten Dijke, P. (2011). TGFbeta activates mitogen- and stress-activated protein kinase-1 (MSK1) to attenuate cell death. The Journal of Biological Chemistry, 286(7), 5003-11. https://doi.org/10.1074/jbc.M110.167379
2010
- Lönn, P., van der Heide, L. P., Dahl, M., Hellman, U., Heldin, C.-H., & Moustakas, A. (2010). PARP-1 attenuates Smad-mediated transcription. Molecular Cell, 40(4), 521-32. https://doi.org/10.1016/j.molcel.2010.10.029
2006
- van der Heide, L. P., Ramakers, G. M. J., & Smidt, M. P. (2006). Insulin signaling in the central nervous system: learning to survive. Progress in Neurobiology, 79(4), 205-21. https://doi.org/10.1016/j.pneurobio.2006.06.003
2005
- van der Heide, L. P., & Smidt, M. P. (2005). Regulation of FoxO activity by CBP/p300-mediated acetylation. Trends in Biochemical Sciences, 30(2), 81-6. https://doi.org/10.1016/j.tibs.2004.12.002
- van der Heide, L. P., Jacobs, F. M. J., Burbach, J. P. H., Hoekman, M. F. M., & Smidt, M. P. (2005). FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling. Biochemical Journal, 391(Pt 3), 623-9. https://doi.org/10.1042/BJ20050525
- van der Heide, L. P., Kamal, A., Artola, A., Gispen, W. H., & Ramakers, G. M. J. (2005). Insulin modulates hippocampal activity-dependent synaptic plasticity in a N-methyl-d-aspartate receptor and phosphatidyl-inositol-3-kinase-dependent manner. Journal of neurochemistry, 94(4), 1158-66. https://doi.org/10.1111/j.1471-4159.2005.03269.x
2004
- Van Der Heide, L. P., Hoekman, M. F. M., & Smidt, M. P. (2004). The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation. Biochemical Journal, 380(Pt 2), 297-309. https://doi.org/10.1042/BJ20040167
2003
- Jacobs, F. M. J., van der Heide, L. P., Wijchers, P. J. E. C., Burbach, J. P. H., Hoekman, M. F. M., & Smidt, M. P. (2003). FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. The Journal of Biological Chemistry, 278(38), 35959-67. https://doi.org/10.1074/jbc.M302804200
- van der Heide, L. P., Hoekman, M. F., Biessels, G. J., & Gispen, W. H. (2003). Insulin inhibits extracellular regulated kinase 1/2 phosphorylation in a phosphatidylinositol 3-kinase (PI3) kinase-dependent manner in Neuro2a cells. Journal of neurochemistry, 86(1), 86-91. https://doi.org/10.1046/j.1471-4159.2003.01828.x
2002
- Biessels, G. J., van der Heide, L. P., Kamal, A., Bleys, R. L. A. W., & Gispen, W. H. (2002). Ageing and diabetes: implications for brain function. European Journal of Pharmacology, 441(1-2), 1-14. https://doi.org/10.1016/s0014-2999(02)01486-3
- Sagt, C. M. J., Müller, W. H., van der Heide, L., Boonstra, J., Verkleij, A. J., & Verrips, C. T. (2002). Impaired cutinase secretion in Saccharomyces cerevisiae induces irregular endoplasmic reticulum (ER) membrane proliferation, oxidative stress, and ER-associated degradation. Applied and Environmental Microbiology, 68(5), 2155-60. https://doi.org/10.1128/AEM.68.5.2155-2160.2002
2023
- Douma, E. H. (2023). Replenishing dopamine in Parkinson’s disease: Tyrosine hydroxylase Ser40 phosphorylation and phosphodiesterase inhibition. [Thesis, fully internal, Universiteit van Amsterdam]. [details]
- Stoop, J. (2023). Discharging dopamine: Boosting endogenous tyrosine hydroxylase activity as a treatment for Parkinson's disease. [Thesis, externally prepared, Universiteit van Amsterdam]. [details]
2021
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Ancillary activities
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http://macrobianbiotech.com/
Founder and CEO -
Parkinnova Therapeutics
Co-CEO
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http://macrobianbiotech.com/
Stoop, J., Douma, E. H., van der Vlag, M., Smidt, M. P., & van der Heide, L. P. (2023). Tyrosine hydroxylase phosphorylation is under the control of serine 40. Journal of neurochemistry, 167(3), 376-393.