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Study of the cellular and molecular effects of SARS-CoV-2 viral proteins on human models of Parkinson’s Disease

Nerea Urrestizala Arenaza

BBioH & Laboratory of GTPases and Neurosignalling, ACHUCARRO

13 Sep 2024 13:00

Aketxe Room, Sede Building, Leioa

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Brain organoids are tridimensional cultures that imitate the spatial and cellular organization of a particular brain region. Organoids can be generated from Induced Pluripotent Stem Cells (iPSC) derived from patients’ skin fibroblasts, which makes them useful tools for studying the development, functioning and pathology of human brain. By combining specific small molecules, iPSCs can be differentiated into any type of neural cell with region-specific properties. Parkinson’s Disease (PD) is a progressive neurodegenerative disorder which results from the destruction of dopaminergic neurons of the nigrostriatal pathway. Evidence gathered over the past few centuries suggests that certain viral infections, such as those caused by HIV, Japanese encephalitis virus or Dengue virus, may affect the nigrostriatal pathway and cause some of the most habitual symptoms of PD, such as tremors, bradykinesia or postural instability. The common denominator among all these triggers could be neuroinflammation, whose key role in the origin and development of many neurodegenerative diseases has already been amply demonstrated. Following the pandemic that swept the globe in 2020, SARS-CoV-2 infection has also been postulated as a possible trigger or accelerator of PD. SARS-CoV-2 has left neurological or psychiatric sequelae in at least 7% of the population, and several clinical reports have linked it to the development of parkinsonian symptoms, and have even proposed it as a cause of some cases of idiopathic PD. The aim of this study is the generation and characterization of both midbrain organoids and nigrostriatal assembloids to study the potential relationship between SARS-CoV-2 infection and PD. More specifically, the study aims to analyze the interaction of SARS-CoV-2 viral protein Spike with neural cells and its functional consequences, especially those related to the dopaminergic pathway. To this end, we optimized a protocol for the generation of midbrain organoids that suited the needs of the project, and results were validated by immunofluorescence assay, qPCR, electron microscopy and electrophysiology. In addition, we designed and generated recombinant proteins based on different regions of Spike and its receptor in human cells, ACE2. These tools will allow us to study the interactions between these two proteins in vitro, the consequences of those interaction on different neural cell types and the neuroprotective potential of preventing them by sequestering viral proteins.