Parallel neurodegenerative phenotypes in sporadic Parkinson’s disease fibroblasts and midbrain dopamine neurons

• Published in: Progress in neurobiology Vol. 229; p. 102501
• Main Authors: Corenblum, MJ, McRobbie-Johnson, A., Carruth, E., Bernard, K., Luo, M., Mandarino, LJ, Peterson, S., Sans-Fuentes, MA, Billheimer, D., Maley, T., Eggers, ED, Madhavan, L.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2023
• Subjects: Aging; alpha-Synuclein - metabolism; Dopaminergic Neurons - metabolism; Fibroblasts - metabolism; Human Induced Pluripotent Stem Cells; Humans; Induced Pluripotent Stem Cells; Mesencephalon - metabolism; Midbrain Dopamine Neurons; Mitochondrial Dysfunction; Parkinson Disease - metabolism; Parkinson's disease; Phenotype; Skin fibroblasts; Aging; Skin fibroblasts; Mitochondrial Dysfunction; Midbrain Dopamine Neurons; Parkinson's disease; Human Induced Pluripotent Stem Cells
• ISSN: 0301-0082; 1873-5118; 1873-5118
• DOI: 10.1016/j.pneurobio.2023.102501

Understanding the mechanisms causing Parkinson’s disease (PD) is vital to the development of much needed early diagnostics and therapeutics for this debilitating condition. Here, we report cellular and molecular alterations in skin fibroblasts of late-onset sporadic PD subjects, that were recapitulated in matched induced pluripotent stem cell (iPSC)-derived midbrain dopamine (DA) neurons, reprogrammed from the same fibroblasts. Specific changes in growth, morphology, reactive oxygen species levels, mitochondrial function, and autophagy, were seen in both the PD fibroblasts and DA neurons, as compared to their respective controls. Additionally, significant alterations in alpha synuclein expression and electrical activity were also noted in the PD DA neurons. Interestingly, although the fibroblast and neuronal phenotypes were similar to each other, they differed in their nature and scale. Furthermore, statistical analysis revealed potential novel associations between various clinical measures of the PD subjects and the different fibroblast and neuronal data. In essence, these findings encapsulate spontaneous, in-tandem, disease-related phenotypes in both sporadic PD fibroblasts and iPSC-based DA neurons, from the same patient, and generates an innovative model to investigate PD mechanisms with a view towards rational disease stratification and precision treatments. [Display omitted] •Sporadic PD fibroblasts, and iPSC-based DA neurons from the same fibroblasts, show spontaneous, in tandem, phenotypes.•Several changes in growth, viability, ROS, mitochondria, and autophagy are seen in both the fibroblasts and DA neurons.•Fibroblasts generally showed worse phenotypes although the DA neurons expressed greater mitochondrial vulnerabilities.•PD DA neurons exhibited altered electrophysiological profiles.•Concomitant use of different peripheral and central iPSC-based neural cell-types may help model PD more comprehensively.