Genome Biology of Neurodegenerative Diseases

N. N.

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).

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.).

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