Summary: Researchers have launched a comprehensive overview of protein expression in the brain. A newly launched open-access database is available for researchers to use.
Source: Karolinska Institute
An international team of scientists led by researchers at Karolinska Institutet in Sweden has launched a comprehensive overview of all proteins expressed in the brain, published today in the journal Science. The open-access database offers medical researchers an unprecedented resource to deepen their understanding of neurobiology and develop new, more effective therapies and diagnostics targeting psychiatric and neurological diseases.
The brain is the most complex organ of our body, both in structure and function. The new Brain Atlas resource is based on the analysis of nearly 1,900 brain samples covering 27 brain regions, combining data from the human brain with corresponding information from the brains of the pig and mouse. It is the latest database released by the Human Protein Atlas (HPA) program which is based at the Science for Life Laboratory (SciLifeLab) in Sweden, a joint research centre aligned with KTH Royal Institute of Technology, Karolinska Institutet, Stockholm University and Uppsala University. The project is a collaboration with the BGI research centre in Shenzhen and Qingdao in China and Aarhus University in Denmark.
“As expected the blueprint for the brain is shared among mammals, but the new map also reveals interesting differences between human, pig and mouse brains,” says Mathias Uhlén, Professor at the Department of Protein Science at KTH Royal Institute of Technology, Visiting professor at the Department of Neuroscience at Karolinska Institutet and Director of the Human Protein Atlas effort.
The cerebellum emerged in the study as the most distinct region of the brain. Many proteins with elevated expression levels in this region were found, including several associated to psychiatric disorders supporting a role of the cerebellum in the processing of emotions.
“Another interesting finding is that the different cell types of the brain share specialised proteins with peripheral organs,” says Dr. Evelina Sjöstedt, researcher at the Department of Neuroscience at Karolinska Institutet and first author on the paper. “For example, astrocytes, the cells that ‘filter’ the extracellular environment in the brain share a lot of transporters and metabolic enzymes with cells in the liver that filter the blood.”
When comparing the neurotransmitter systems, responsible for the communication between neurons, some clear differences between the species could be identified.
“Several molecular components of neurotransmitter systems, especially receptors that respond to released neurotransmitters and neuropeptides, show a different pattern in humans and mice,” says Dr. Jan Mulder, group leader of the Human Protein Atlas brain profiling group and researcher at the Department of Neuroscience at Karolinska Institutet. “This means that caution should be taken when selecting animals as models for human mental and neurological disorders.”
For selected genes/proteins, the Brain Atlas also contains microscopic images showing the protein distribution in human brain samples and detailed, zoomable maps of protein distribution in the mouse brain.
The Human Protein Atlas started in 2003 with the aim to map all of the human proteins in cells, tissues and organs (the proteome). All the data in the knowledge resource is open access allowing scientists both in academia and industry to freely use the data for the exploration of the human proteome.
Funding: The main funding for the research was provided by the Knut and Alice Wallenberg Foundation.
Original Research: Closed access “An atlas of the protein-coding genes in the human, pig and mouse brain”. Evelina Sjöstedt, Wen Zhong, Linn Fagerberg, Max Karlsson, Nicholas Mitsios, Csaba Adori, Per Oksvold, Fredrik Edfors, Agnieszka Limiszewska, Feria Hikmet, Jinrong Huang, Yutao Du, Lin Lin, Zhanying Dong, Ling Yang, Xin Liu, Hui Jiang, Xun Xu, Jian Wang, Huanming Yang, Lars Bolund, Adil Mardinoglu, Cheng Zhang, Kalle von Feilitzen, Cecilia Lindskog, Fredrik Pontén, Yonglun Luo, Tomas Hökfelt, Mathias Uhlén, Jan Mulder. Science doi:10.1126/science.aay5947.
An atlas of the protein-coding genes in the human, pig and mouse brain
INTRODUCTION The brain is the most complex organ of the mammalian body, boasting a diverse physiology combined with intricate cellular organization. In an effort to expand our basic understanding of the neurobiology of the brain and its diseases, we performed a comprehensive molecular dissection of the main regions of the human, pig, and mouse brain using transcriptomics and antibody-based mapping. With this approach, we have identified regional expression profiles and observed similarities and differences in expression levels between these three mammalian species.
RATIONALE There is a need for a comprehensive overview of genes expressed in the mammalian brain categorized by organ, brain region, and species specificity. To address this need, a brain-centered knowledge resource of RNA and protein expression in the brain of three mammalian species has been created and used for cell topological analysis, systems modeling, and data integration. The regional expression of all protein-coding genes is reported, and this classification is integrated with results from the analysis of tissues and organs of the whole human body. All generated data, including high-resolution images and metadata, have been made publicly available in an open-access Human Protein Atlas (HPA) Brain Atlas. RESULTS The global analysis suggests similar regional organization and expression patterns in the three mammalian species, consistent with the view that basic brain architecture is preserved during mammalian evolution. However, there is considerable variability between species for many neurotransmitter receptors, in particular between human and mouse. This calls for caution when using the mouse as a model system for the human brain, for example, in attempts to develop therapeutic strategies. For some of the brain regions, such as the cerebellum and hypothalamus, the human global expression profile is closer to that of the pig than it is to that of the mouse, suggesting that the pig might be considered a preferred animal model to study many brain processes. We show that many “signature genes” identified previously for specific brain cell types (such as astrocytes, microglia, oligodendrocytes, and neurons) are expressed at even higher levels in peripheral organs. In fact, our results support a view of shared functions between many genes in microglia and immune cells, and a large number of genes previously identified as signature genes for astrocytes are shown to be shared with liver or skeletal muscle. The cerebellum stands out as having a distinct molecular signature with many regionally enriched genes. Several genes suggested to be involved in neuropsychiatric diseases are selectively expressed in the cerebellum.
CONCLUSION The integration of data from several sources has allowed us to combine data from transcriptomics, single-cell genomics, in situ hybridization, and antibody-based protein profiling. This integrative approach for mapping the molecular profiles in the human, pig, and mouse brain has generated a detailed multilevel genome-wide view on the protein-coding genes of the mammalian brain, where we compared tissue specificity across the whole body, as classified in the HPA (www.proteinatlas.org). The open-access HPA Brain Atlas resource offers the opportunity to explore individual genes and classes of genes and their expression profiles in the various parts of the mammalian brain.