Objective: Natural compound libraries are a great source of new chemical molecules that could restore the altered phenotypes in patient derived cells. The objective of this project was to discover compounds that modify the autophagy pathway in the context of a genetic form of PD, which was further validated in midbrain organoids derived from patients with different genetic backgrounds.
Background: Parkinson’s disease (PD) is a neurodegenerative ailment caused by polygenetic factors that converge, among others, in the autophagy pathway. Genes known to cause PD when mutated, such as PINK1, Parkin, VPS35, LRRK2, and SNCA, play a role in autophagy.
Method: Using genetically encoded pH sensors, we engineered healthy and patient iPSC lines to monitor autophagy for screening a library of natural compounds in a high-throughput phenotypic platform with automated high-content image analysis. Identified hits were further selected based on dose response curves. The effects of these compounds on the number of dopaminergic neurons, as well as others features, were assessed in 2D and 3D midbrain organoids.
Results: A library of 640 compounds, the majority of which have been obtained from Australian natural sources, such as fungi, plants, and marine invertebrates, was screened leading to the identification of 9 small molecule compounds that rescued autophagy alterations in cells derived from a patient having the D620N mutation in the VPS35 gene. Three compounds were selected, and further tested in 2D neurons and midbrain organoids derived from patients having mutations in the GBA, SNCA, and MIRO1 genes.
Conclusion: Modifiers of the autophagy pathway activity are interesting candidates for further development as therapeutic molecules to target neurodegeneration in PD.
References: This work will be presented as well in the ADPD 2023 Alzheimer’s & Parkinson’s Diseases Conference, 28/3-1/4/2023.
To cite this abstract in AMA style:J. Jarazo, I. Rosety, C. Serra-Almeida, R. Marques, C. Saraiva, R. Davis, J. Schwamborn. Targeting autophagy to identify novel modulators of Parkinson’s disease using midbrain organoids [abstract]. Mov Disord. 2023; 38 (suppl 1). https://www.mdsabstracts.org/abstract/targeting-autophagy-to-identify-novel-modulators-of-parkinsons-disease-using-midbrain-organoids/. Accessed September 22, 2023.
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MDS Abstracts - https://www.mdsabstracts.org/abstract/targeting-autophagy-to-identify-novel-modulators-of-parkinsons-disease-using-midbrain-organoids/