{"id":1719,"date":"2022-03-17T15:52:06","date_gmt":"2022-03-17T15:52:06","guid":{"rendered":"https:\/\/website.prod.unilu.spikeseed.cloud\/fr\/news\/midbrain-single-cell-sequencing-to-understand-parkinsons-disease\/"},"modified":"2022-03-17T15:52:06","modified_gmt":"2022-03-17T15:52:06","slug":"midbrain-single-cell-sequencing-to-understand-parkinsons-disease","status":"publish","type":"news","link":"https:\/\/www.uni.lu\/fr\/news\/midbrain-single-cell-sequencing-to-understand-parkinsons-disease\/","title":{"rendered":"Midbrain single-cell sequencing to understand Parkinson\u2019s Disease"},"content":{"rendered":"

Researchers from the Luxembourg Centre for Systems Biomedicine (LCSB) at the University of Luxembourg, in collaboration with the Max Planck Institute for Molecular Genetics in Berlin, investigated the different cell types present in the human midbrain to better understand their respective role in Parkinson\u2019s disease.\u00a0\u00a0They examined post-mortem samples from people affected by the disease and from healthy individuals, and generated a unique single-nuclei RNA sequencing dataset. Their results, recently published in the scientific journal\u00a0Brain<\/i>, revealed the existence of a specific cluster of cells in the midbrain of Parkinson\u2019s patients. They also highlighted the role of glial cells \u2013 the non-neuronal cells in the brain \u2013 in the pathology of this movement disorder.<\/p>\n

\nParkinson\u2019s disease in a nutshell<\/h2>\n

Parkinson\u2019s disease (PD) is characterised by the loss of dopaminergic neurons in the midbrain but the exact causes of the disease are still not well understood. These neurons control brain functions like voluntary movement and behavioural processes such as stress. Their degeneration leads to the disease with its classical symptoms: trembling, stiffness and loss of balance and coordination. However, this is not the whole picture: recent findings indicate that other cell types can also be involved in the course of the disease.<\/p>\n

\nSingle-nuclei RNA sequencing of the midbrain<\/h2>\n

To get information about the role of other non-neuronal cell types, the researchers examined the entire cell population of the midbrain. Sections of post-mortem brain tissues donated by five patients with idiopathic PD, meaning the disease has no known cause in their case, and six healthy controls were examined. The scientists took advantage of the recent developments in single-cell technologies and used an approach called single-nuclei RNA sequencing. \u201cWe sequenced 41,000 nuclei in total to obtain a global view of the cell type composition and its contribution to the disease.\u201d explains\u00a0Prof. Anne Gr\u00fcnewald<\/a>, head of the\u00a0Molecular and Functional Neurobiology group<\/a>\u00a0at the LCSB and joint-senior author of the article, along with\u00a0Prof. Malte Spielmann<\/a>\u00a0from the\u00a0Max Planck Institute for Molecular Genetics<\/a>. This is the first single-nuclei RNA sequencing dataset ever obtained from the idiopathic Parkinson\u2019s disease midbrain.<\/p>\n

\nDiscovery of a disease-specific state of neurons<\/h2>\n

Based on the RNA sequencing results, midbrain cells belonging to the main groups found in the brain – glial, neuronal, ependymal and vascular – were sorted into 12 smaller clusters, indicating 12 different cell types (see illustration below). Each cell type was classified based on the expression of specific marker genes and presents different characteristics. One of the identified clusters corresponds to dopaminergic neurons. These cells are characterised by a specific marker called tyrosine hydroxylase (TH) and were underrepresented in the midbrain tissue of Parkinson\u2019s disease patients.<\/p>

\n \n\"\"\n <\/figure>

Interestingly, the researchers also discovered a small population of neuronal cells present in the samples from Parkinson\u2019s patients. This cluster of 120 cells could not be readily classified. \u201cThose cells were almost exclusively found in individuals with Parkinson\u2019s,\u201d points out\u00a0Semra Smaji\u0107, doctoral researcher in the Molecular and Functional Neurobiology group and joint-first author of the article along with Cesar A. Prada-Medina from the Max Planck Institute. \u201cTheir sequencing profile is similar to dopaminergic neurons, in the sense that they are the only two cell types that express the\u00a0CADPS2 gene, but, unlike dopaminergic neurons,\u00a0they also\u00a0show a low expression of TH. Taking all that into consideration, we think that this disease-specific cell type might correspond to degenerating dopaminergic neurons.\u201d Further investigations are now needed to confirm this hypothesis.<\/p>\n

\nReactive microglia: a signature of idiopathic Parkinson\u2019s disease?<\/h2>\n

As a potential factor in the degeneration of dopaminergic neurons is inflammation, the researchers also took a closer look at inflammatory processes in the brain tissues of Parkinson\u2019s patients and healthy individuals. Their analyses revealed differences in microglial cells, the \u201ccleaning personnel\u201d of the brain that digest pathogens or damaged neurons as part of the overall brain maintenance. They are in charge of the brain\u2019s immune system as well and play a key role in inflammation.\u00a0<\/p>

While resting microglia are ramified, they retract their branches and switch to an amoeboid form when assuming their cleaning role or to a reactive state when performing their function in immune defence. The researchers observed changes in the shape of microglia: the cells were less ramified and more amoeboid in the tissues affected by the disease, indicating their activation. Moreover, the microglia population was overrepresented in the patients\u2019 samples, denoting a higher level of inflammation. Additionally, when trying to classify microglia, the team discovered three sub-populations defined by a high expression of genes involved in the inflammatory response linked to neurodegeneration. \u201cTaken together, our results suggest that microglia contribute to the degeneration of dopaminergic neurons and that\u00a0glial activation is a central mechanism\u00a0in idiopathic Parkinson\u2019s disease. It reinforces the relevance of neuroinflammation in the pathology,\u201d explains Prof. Gr\u00fcnewald.<\/p>

\u201cPast studies have mostly focused on neuronal cells in the midbrain. Our unique single-nuclei RNA sequencing dataset now provides the basis for new research approaches investigating the role of different cell types in the disease and for translational programs that aim to develop immunomodulatory therapies,\u201d concludes Prof. Malte Spielmann.<\/p>

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References:<\/p>