Who is to blame? Investigating Genes within the 22q11.2 Deletion Region as potential Risk Factors for Parkinson's Disease using Human iPS Cells and CRISPR Perturbation

• Applicant: Laurin Heinrich, Ph.D.
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases
• Term: from 2021 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 471227244

Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide. Still, the pathogenesis of PD is incompletely understood, and treating PD is limited to symptomatic therapies, which can lead to undesirable long-term side effects. Major limitations in understanding and treating PD is its heterogeneous etiology with genetic as well as environmental risk factors and the challenge that current models of PD do not fully recapitulate all clinical and neuropathological relevant aspects of the disease. The development of new human-derived stem cell models in vitro shed new light on PD pathogenesis and confirmed a neurodevelopmental link to neurodegeneration of PD. Discovery and investigation of new genetic risk factors contributing to neurodevelopmental defects and increased risk for the development of PD might provide an entry point towards better understanding PD pathogenesis.Only recently one of the most common deletion syndromes (~1:2,000-4,000 live births) the 22q11.2DS was found to constitute a significant genetic risk factor for developing early-onset PD. Since PD patients with 22q11.2DS can develop similar symptoms as compared to patients with sporadic PD, this indicates common disease mechanisms and pathways triggered by the dysregulation of affected genes in the 22q11 deletion region. We hypothesize that identifying genes within the 22q.11.2 deletion that are responsible for developmental defects described for 22q.11.2DS will enable the discovery of new target genes involved in PD pathology and might bear the potential to uncover mechanisms that are essential in developing future treatment strategies.The overall goal of this fellowship is to increase our understanding of genes within the 22q11.2 deletion region and their potential role in 22q11.2DS and 22q11.2DS PD. [Objective 1] I will build an in vitro neuronal network relevant for 22q11.2DS with neurons derived from human stem cells from 22q11.2DS patients and probe for well-described disease-associated phenotypes by using high-content imaging, molecular biological readouts, and electrophysiological recordings with a novel high-content microelectrode array chip. [Objective 2] I will further generate iPSCs expressing Clustered Regularly Interspaced Short Palindromic Repeats activation (CRISPRa) or interference (CRISPRi) machinery by genetic cloning to regulate gene expression from endogenous loci within the 22q11DS. [Objective 3] This will allow me to identify specific genes inside the 22q11.2 deletion involved in phenotypes detected (in Objective 1) for 22q11.2DS PD by employing a CRISPR-modifier screen in the developed neuronal networks.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Dr. Birgitt Schüle