Characterizing Genetic Risk Variants in Dopaminergic Neurons: Cohort of 95 PPMI Participants

Francis Webb^*
*Correspondence: Francis Webb, Department of Translational Genomics, University of Southern California, Los Angeles, USA, Email:

Keywords

Genetic risk variants • Dopaminergic neurons • 95 PPMI

Introduction

Understanding the intricate relationship between genetics and neurodegenerative disorders has been a longstanding challenge in the field of neuroscience. Parkinson's disease (PD), characterized by the loss of dopaminergic (DA) neurons in the substantia nigra, has been associated with both genetic and environmental factors. Leveraging the groundbreaking potential of induced pluripotent stem cells (iPSCs), researchers have embarked on a groundbreaking study involving 95 participants from the Parkinson's Progression Markers Initiative (PPMI) to explore the differentiation of iPSCs into DA neurons and investigate the impact of varying genetic risks. This pioneering research aims to shed light on the cellular context of genetic risk in PD pathogenesis.

Literature Review

The study recruited a diverse cohort of 95 PPMI participants, comprising individuals with varying levels of genetic risk associated with PD. Skin fibroblasts or peripheral blood cells were collected from each participant and reprogrammed into iPSCs using established protocols. These iPSCs were then differentiated into DA neurons using carefully tailored differentiation protocols that mimic the natural developmental processes in the human brain. To assess the varying genetic risks, the study employed state-of-the-art genetic profiling techniques such as whole-genome sequencing, targeted genotyping and single-nucleotide polymorphism (SNP) analysis. By identifying key genetic variants and risk alleles in each participant, the researchers aimed to correlate these findings with the observed characteristics of the differentiated DA neurons. Using a combination of growth factors, small molecules and precise culture conditions, the iPSCs were guided through stages that recapitulated the development of DA neurons. By monitoring specific markers associated with midbrain dopaminergic development, such as tyrosine hydroxylase (TH) and dopamine transporter (DAT), the researchers confirmed the successful differentiation and maturation of iPSCs into functional DA neurons.

Discussion

To comprehensively understand the impact of varying genetic risks on DA neuron development, the researchers performed thorough phenotypic characterization. This involved assessing neuronal morphology, electrophysiological properties and neurotransmitter release capabilities of the differentiated DA neurons. Comparative analyses were conducted to uncover potential variations associated with specific genetic risk profiles. By combining the genetic profiling data with the phenotypic characterization of the differentiated DA neurons, the study aimed to uncover valuable insights into the impact of genetic risk variants on the pathogenesis of PD. It is anticipated that this research will reveal potential links between specific genetic variants and altered neuronal function, providing a deeper understanding of the disease mechanisms and potential therapeutic targets.

The differentiation of iPSCs into DA neurons from a cohort of 95 PPMI participants with varying genetic risks represents a crucial step forward in unraveling the complex interplay between genetics and PD pathogenesis. This pioneering research has the potential to identify key genetic variants associated with PD, shedding light on the underlying mechanisms of the disease and opening up new avenues for targeted therapeutic interventions. Ultimately, this study brings us closer to personalized medicine approaches and a deeper understanding of neurodegenerative disorders.

In the realm of neurodegenerative disorders, the etiology and pathogenesis of Parkinson's disease (PD) have long been subjects of intense research. The emergence of induced pluripotent stem cells (iPSCs) has revolutionized the study of human neuronal development and disease modeling. Leveraging this groundbreaking technology, researchers have successfully differentiated iPSCs into dopaminergic (DA) neurons, providing a unique cellular context to explore the impact of genetic risk factors. This article explores the remarkable potential of DA neurons derived from human iPSCs in unraveling the intricate relationship between genetic risk and PD.

Induced pluripotent stem cells hold immense promise in the field of regenerative medicine and disease modeling. By reprogramming somatic cells, such as skin fibroblasts or peripheral blood cells, iPSCs can be generated, bypassing the ethical concerns associated with embryonic stem cells. These iPSCs possess the ability to differentiate into any cell type in the human body, including the highly specialized DA neurons crucial for PD research. Differentiating iPSCs into DA neurons offers a unique opportunity to recapitulate disease processes in a laboratory setting. By inducing specific developmental pathways, iPSCs can be guided to follow the natural progression of DA neuron development. This process involves the sequential activation of key signaling pathways and the expression of specific transcription factors, ultimately leading to the generation of functional DA neurons. Genetic factors play a significant role in the development of PD. Researchers have identified several genes and genetic variants associated with an increased risk of developing the disease. However, the precise mechanisms through which these genetic risk factors contribute to the pathogenesis of PD remain poorly understood. This is where iPSC-derived DA neurons provide invaluable insights.

By differentiating iPSCs from individuals with varying genetic risks for PD, researchers can generate a diverse pool of DA neurons that mirror the genetic landscape of the disease. These iPSC-derived DA neurons can then be extensively characterized and compared, allowing researchers to investigate the impact of specific genetic variants on neuronal morphology, function and vulnerability to degeneration. The development of sophisticated techniques, such as electrophysiological recordings, calcium imaging and neurotransmitter release assays, enables researchers to probe the functional properties of iPSC-derived DA neurons. By studying the electrical activity, synaptic connectivity and response to pharmacological agents, researchers can gain insights into how genetic risk factors influence the behavior and integrity of these neurons [1-6].

Conclusion

The ability to generate iPSC-derived DA neurons from individuals with known genetic risk factors holds immense promise for personalized medicine approaches. By understanding the cellular context of specific genetic variants, researchers can develop targeted therapies tailored to an individual's genetic makeup. Additionally, iPSC-derived DA neurons serve as valuable tools for drug screening and testing, enabling the identification of potential therapeutic compounds that can modulate disease-related processes. The differentiation of iPSCs into DA neurons provides a remarkable platform for investigating the cellular context of genetic risk in PD. By leveraging this innovative technology, researchers can unravel the intricate relationship between genetic variants and disease pathogenesis. The valuable insights gained from studying iPSCderived DA neurons offer new avenues for personalized medicine approaches and the development of novel therapeutics. Ultimately, this research paves the way for a deeper understanding of PD and the potential to transform patient care and outcomes in the future.

Acknowledgement

None.

Conflict of Interest

None.

References

1. Bressan, Elisangela, Xylena Reed, Vikas Bansal and Elizabeth Hutchins, et al. "The Foundational data initiative for Parkinson’s disease (FOUNDIN-PD): Enabling efficient translation from genetic maps to mechanism." bioRxiv (2021): 2021-06.

Google Scholar, Crossref, Indexed at

2. Huh, Young Eun, Hyejung Park, Ming Sum Ruby Chiang and Idil Tuncali, et al. "Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson’s disease enrolled in PPMI." : NPJ Parkinson's dis 7 (2021): 102.

Google Scholar, Crossref, Indexed at

3. Birkenbihl, Colin, Ashar Ahmad, Nathalie J Massat and Tamara Raschka, et al. "Artificial intelligence-based clustering and characterization of Parkinson's disease trajectories." Sci Rep 13 (2023): 2897.

Google Scholar, Crossref, Indexed at

4. Latourelle, Jeanne C, Michael T Beste, Tiffany C Hadzi and Robert E Miller, et al. "Large-scale identification of clinical and genetic predictors of motor progression in patients with newly diagnosed Parkinson's disease: A longitudinal cohort study and validation." Lancet Neurol 16 (2017): 908-916.

Google Scholar, Crossref, Indexed at

5. Senkevich, Konstantin, Cornelia E. Zorca, Aliza Dworkind and Uladzislau Rudakou, et al. "GALC variants affect galactosylceramidase enzymatic activity and risk of Parkinson’s disease." Brain 146 (2023): 1859-1872.

Google Scholar, Crossref, Indexed at

6. Robak, Laurie A, Iris E. Jansen, Jeroen Van Rooij and André G. Uitterlinden, et al. "Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease." Brain 140 (2017): 3191-3203.

Google Scholar, Crossref, Indexed at