Genome Biology of Neurodegenerative Diseases
Prof. Dr. Peter Heutink
Group Leader and Site Speaker
Professor of Genome Biology of Neurodegenerative diseases at the Hertie Institute for Clinical Brain Research in Tübingen & visiting researcher at RIKEN Center for Life Science Technologies, Yokohama, Japan
Otfried-Müller-Str. 23
72076 Tübingen

peter.heutink@dzne.de
 +49 7071 9254-050

Areas of investigation/research focus

The underlying causes for neurodegenerative disease are still largely unknown but there is clear evidence that genetic risk factors play an important role. The identification of such genetic risk factors provides us with important starting points to study the molecular processes that lead to disease as they act at the very beginning of the disease process.

The research focus of our group is therefore to identify genetic risk factors for neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Frontal-Temporal Dementia/Motor Neuron Disease, Progressive Supranuclear Palsy and Ataxia in close collaboration with our clinical partners and to characterize the biological consequences of these mutations and risk factors by using molecular biology and genomic approaches. (For an essay on our approaches, see; Jain S, Heutink P. From single genes to gene networks: high-throughput-high-content screening for neurological disease. Neuron. 2010 Oct 21; 68(2):207-17).

 more Infos

Finding new genetic risk factors

To identify new genetic risk factors we investigate families with neurodegenerative diseases as well as large cohorts of sporadic cases using SNP array genotyping and Massive Parallel Sequencing (MPS) approaches such as whole exome and whole genome sequencing. Prof. Heutink is currently is a member of the International Parkinsons Disease Genomics Consortium (IPDGC) and the International FTD genetics Consortium.

The data analysis is performed in close collaboration with Dr. Javier Simón-Sánchez who leads the joined research group Genetics and Epigenetics of Neurodegeneration. The research group "Genetics and Epigenetics of Neurodegeneration" has been jointly established at the Department of Neurodegenerative Diseases within the Hertie Institute for Clinical Brain Research (HIH) and the research group Genome Biology at the German Center for Neurodegenerative Diseases (DZNE). The group has a primary interest in the genetics and genomics of neurodegenerative disorders such as Parkinson's disease (PD), Progressive Supranuclear Palsy (PSP) or Frontotemporal Dementias (FTD). The research group "Genetics and Epigenetics of Neurodegeneration" aims to translate the meaning of previous genetic findings into testable biological hypotheses. Thus, we aim to expand previous work on genetic analysis to a more broader bioinformatic focus by integration of GWAS hits and Next Generation Sequencing (NGS) variants derived from whole-exome, targeted re-sequencing and whole genome sequencing approaches, with expression data from RNA sequencing (RNAseq) and Capped Analysis of Gene Expression (CAGE) experiments. This, in combination with the aforementioned epigenetic data, will help to further understand the genetic (or genomic) mechanisms underlying the etiology of various neurodegenerative disorders. 

Understanding the biology of genetic risk factors

The identification of new genetic risk factors allows us to investigate the biological consequences of the underlying mutations to the molecular pathways in which they function in human post-mortem brain and cellular models including primary neurons or patient derived induced pluripotent stem (iPS) cells. We use two main approaches to follow up these findings and to study the biological consequences of genetic mutations.

One approach aims to dissect and study the gene networks in which the risk factors are functioning by studying gene expression in patient post-mortem brain and patient derived cell lines such as iPS derived neurons. We aim to model complete transcriptional networks to identify key regulators of the affected pathways. We perform MPS based gene expression analysis for coding and noncoding RNA expression (RNAseq, CAGE) and combine this with epigenetic and proteomic data using integrative bioinformatics analysis. The work is performed in close collaboration with the Dutch Brain Bank and the group of Applied Genomics for Neurodegenerative diseases at the DZNE-Tübingen led by Dr. Patrizia Rizzu and the research group led by  Dr.  Javier Simón-Sánchez Genetics and Epigenetics of Neurodegeneration.

To validate and extend our findings and to understand the function of identified genes and non-coding RNAs we follow a second approach using cellular models such as neuroblastoma lines and neuronal differentiated patient derived iPS cell in which we can selectively overexpress or silence newly identified genetic risk factors or key regulatory genes and transcripts form identified pathways. This allows us to study the pathways that act downstream of these genes. We use a combination of “read outs” such as gene expression, epigenetic changes and imaging of reporter constructs or cell organelle morphology.

Our iPS based models are either derived from patients blood or fibroblasts or by using CRISPR/Cas9 genome editing. For our gene silencing experiments and cellular screens we use a genome wide lentiviral shRNA library originally developed by the Broad Institute, and CRISPR/Cas9 pooled libraries.

For our cellular screens, we have developed an automated cell culture system with integrated fluorescent and confocal microscopy to allow for high-throughput high-content cellular screening. This system allows us to perform high throughput cellular screens in which we can systematically perturb and analyse the effects of large numbers of genes in a longitudinal setup. The current system at Tübingen has been developed using our experience of an earlier system (Jain SSondervan D, Rizzu, P, Bochdanovits, Z, Caminda D, Heutink P. (2011). The complete automation of cell culture: Improvements for high-throughput and high-content screening. Journal of Biomolecular Screening 16(8): 932-9; Jain, S., van Kesteren, R. E., Heutink, P. High Content Screening in Neurodegenerative Diseases. J. Vis. Exp (59), e3452, doi:10.3791/3452 (2012).The system is available for other users. Please contact Prof. P. Heutink for more information.

Our integrative approach focuses on the translation of genetic findings into biologically verifiable hypotheses in cellular and animal models. Identified genes and gene networks can then be systematically explored to identify the most suitable targets for therapy development. (Jansen IE et al. Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing. Genome Biol. 2017 Jan 30;18(1):22. doi: 10.1186/s13059-017-1147-9.).

Schlüsselpublikationen

Iris E. Jansen, Hui Ye, Sasja Heetveld, Marie C. Lechler, Helen Michels, Renée I. Seinstra, Steven J. Lubbe, Valérie Drouet, Suzanne Lesage, Elisa Majounie, J.Raphael Gibbs, Mike A. Nalls, Mina Ryten, Juan A. Botia, Jana Vandrovcova, Javier Simon-Sanchez, Melissa Castillo-Lizardo, Patrizia Rizzu, Cornelis Blauwendraat, Amit K. Chouhan, Yarong Li, Puja Yogi, Najaf Amin, Cornelia M. van Duijn, Huw R. Morris, Alexis Brice, Andrew B. Singleton, Della C. David, Ellen A. Nollen, Shushant Jain, Joshua M. Shulman, Peter Heutink, Dena G. Hernandez, Sampath Arepalli, Janet Brooks, Ryan Price, Aude Nicolas, Sean Chong, Mark R. Cookson, Allissa Dillman, Matthew Moore, Bryan J. Traynor, Andrew B. Singleton, Vincent Plagnol, Nicholas W Wood, Una-Marie Sheerin, Jose M Bras, Gavin Charlesworth, Michelle Gardner, Rita Guerreiro, Daniah Trabzuni, John Hardy, Manu Sharma, Mohamad Saad, Javier Simón-Sánchez, Claudia Schulte, Jean Christophe Corvol, Alexandra Dürr, Marie Vidailhet, Sigurlaug Sveinbjörnsdóttir, Roger Barker, Caroline H Williams-Gray, Yoav Ben-Shlomo, Henk W. Berendse, Karin D. van Dijk, Daniela Berg, Kathrin Brockmann, Isabel Wurster, Walter Mätzler, Thomas Gasser, Maria Martinez, Rob M. A. de Bie, Alessandro Biffi, Daan Velseboer, Bas Bloem, Bart Post, Mirdhu Wickremaratchi, Bart van de Warrenburg, Zoltan Bochdanovits, Michael Bonin, Hjörvar Pétursson, Olaf Riess, David J. Burn, Steven Lubbe, J Mark Cooper, Alisdair McNeill, Anthony Schapira, Codrin Lungu, Honglei Chen, Jing Dong, Patrick F. Chinnery, Gavin Hudson, Carl E. Clarke, Catriona Moorby, Carl Counsell, Philippe Damier, Jean-François Dartigues, Panos Deloukas, Emma Gray, Sarah Edkins, Sarah E. Hunt, Simon Potter, Avazeh Tashakkori-Ghanbaria, Günther Deuschl, Delia Lorenz, David T. Dexter, Frank Durif, Jonathan R. Evans, Cordelia Langford, Thomas Foltynie, Alison Goate, Clare Harris, Jacobus J. van Hilten, Albert Hofman, Albert Hollenbeck, Janice Holton, Michele Hu, Xuemei Huang, Thomas Illig, Pálmi V. Jónsson, Jean-Charles Lambert, Sean S. O'Sullivan, Tamas Revesz, Karen Shaw, Andrew Lees, Peter Lichtner, Patricia Limousin, Grisel Lopez, Valentina Escott-Price, Justin Pearson, Nigel Williams, Ese Mudanohwo, Joel S. Perlmutter, Pierre Pollak, Fernando Rivadeneira, André G. Uitterlinden, Stephen Sawcer, Hans Scheffer, Ira Shoulson, Joshua Shulman, Colin Smith, Robert Walker, Chris C. A. Spencer, Amy Strange, Hreinn Stefánsson, Francesco Bettella, Kári Stefánsson, Joanna D. Stockton, Kevin Talbot, Carlie M. Tanner, François Tison, Sophie Winder-Rhodes, Kailash Bhatia. Discovery and functional prioritization of Parkinson's disease candidate genes from large-scale whole exome sequencing. Genome Biology. 2017 Jan 29; 18 doi: 10.1186/s13059-017-1147-9
FANTOM Consortium and the RIKEN PMI and CLST (DGT), Forrest AR, Kawaji H, Rehli M, Baillie JK, de Hoon MJ, Haberle V, Lassmann T, Kulakovskiy IV, Lizio M, Itoh M, Andersson R, Mungall CJ, Meehan TF, Schmeier S, Bertin N, Jørgensen M, Dimont E, Arner E, Schmidl C, Schaefer U, Medvedeva YA, Plessy C, Vitezic M, Severin J, Semple C, Ishizu Y, Young RS, Francescatto M, Alam I, Albanese D, Altschuler GM, Arakawa T, Archer JA, Arner P, Babina M, Rennie S, Balwierz PJ, Beckhouse AG, Pradhan-Bhatt S, Blake JA, Blumenthal A, Bodega B, Bonetti A, Briggs J, Brombacher F, Burroughs AM, Califano A, Cannistraci CV, Carbajo D, Chen Y, Chierici M, Ciani Y, Clevers HC, Dalla E, Davis CA, Detmar M, Diehl AD, Dohi T, Drabløs F, Edge AS, Edinger M, Ekwall K, Endoh M, Enomoto H, Fagiolini M, Fairbairn L, Fang H, Farach-Carson MC, Faulkner GJ, Favorov AV, Fisher ME, Frith MC, Fujita R, Fukuda S, Furlanello C, Furino M, Furusawa J, Geijtenbeek TB, Gibson AP, Gingeras T, Goldowitz D, Gough J, Guhl S, Guler R, Gustincich S, Ha TJ, Hamaguchi M, Hara M, Harbers M, Harshbarger J, Hasegawa A, Hasegawa Y, Hashimoto T, Herlyn M, Hitchens KJ, Ho Sui SJ, Hofmann OM, Hoof I, Hori F, Huminiecki L, Iida K, Ikawa T, Jankovic BR, Jia H, Joshi A, Jurman G, Kaczkowski B, Kai C, Kaida K, Kaiho A, Kajiyama K, Kanamori-Katayama M, Kasianov AS, Kasukawa T, Katayama S, Kato S, Kawaguchi S, Kawamoto H, Kawamura YI, Kawashima T, Kempfle JS, Kenna TJ, Kere J, Khachigian LM, Kitamura T, Klinken SP, Knox AJ, Kojima M, Kojima S, Kondo N, Koseki H, Koyasu S, Krampitz S, Kubosaki A, Kwon AT, Laros JF, Lee W, Lennartsson A, Li K, Lilje B, Lipovich L, Mackay-Sim A, Manabe R, Mar JC, Marchand B, Mathelier A, Mejhert N, Meynert A, Mizuno Y, de Lima Morais DA, Morikawa H, Morimoto M, Moro K, Motakis E, Motohashi H, Mummery CL, Murata M, Nagao-Sato S, Nakachi Y, Nakahara F, Nakamura T, Nakamura Y, Nakazato K, van Nimwegen E, Ninomiya N, Nishiyori H, Noma S, Noma S, Noazaki T, Ogishima S, Ohkura N, Ohimiya H, Ohno H, Ohshima M, Okada-Hatakeyama M, Okazaki Y, Orlando V, Ovchinnikov DA, Pain A, Passier R, Patrikakis M, Persson H, Piazza S, Prendergast JG, Rackham OJ, Ramilowski JA, Rashid M, Ravasi T, Rizzu P, Roncador M, Roy S, Rye MB, Saijyo E, Sajantila A, Saka A, Sakaguchi S, Sakai M, Sato H, Savvi S, Saxena A, Schneider C, Schultes EA, Schulze-Tanzil GG, Schwegmann A, Sengstag T, Sheng G, Shimoji H, Shimoni Y, Shin JW, Simon C, Sugiyama D, Sugiyama T, Suzuki M, Suzuki N, Swoboda RK, 't Hoen PA, Tagami M, Takahashi N, Takai J, Tanaka H, Tatsukawa H, Tatum Z, Thompson M, Toyodo H, Toyoda T, Valen E, van de Wetering M, van den Berg LM, Verado R, Vijayan D, Vorontsov IE, Wasserman WW, Watanabe S, Wells CA, Winteringham LN, Wolvetang E, Wood EJ, Yamaguchi Y, Yamamoto M, Yoneda M, Yonekura Y, Yoshida S, Zabierowski SE, Zhang PG, Zhao X, Zucchelli S, Summers KM, Suzuki H, Daub CO, Kawai J, Heutink P, Hide W, Freeman TC, Lenhard B, Bajic VB, Taylor MS, Makeev VJ, Sandelin A, Hume DA, Carninci P, Hayashizaki Y. A promoter-level mammalian expression atlas. Nature. 2014 Mar 27; 507:462-70. doi: 10.1038/nature13182
Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, ..., Heutink P et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011 Jan 01; 72:257-68. doi: 10.1016/j.neuron.2011.09.010
Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2013 Jan 10; 299:256-9.
Hutton M, Lendon CL, Rizzu P*, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P *joint first author. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998 Jun 18; 393:702-5.

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