Reduced synaptic activity and dysregulated extracellular matrix pathways are common phenotypes in midbrain neurons derived from sporadic and mutation-associated Parkinson's disease patients

Stern, S.; Lau, S.; Manole, A.; Rosh, I.; Percia, M.; Ben-Ezer, R.; Shokhirev, M.; Qiu, F.; Schafer, S.; Mansour, A.; Stern, T.; Ofer, P.; Stern, Y.; Diniz, A. M.; Moore, L. R.; Nayak, R.; Aicher, A.; Rhee, A.; Wong, T.; Nguyen, T.; Linker, S. B.; Winner, B.; Freitas, B.; Jones, E.; Bardy, C.; Brice, A.; Winkler, J.; Marchetto, M. C.; Gage, F. H.

doi:10.1101/2021.12.31.474654

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bioRxiv · 10.1101/2021.12.31.474654

Reduced synaptic activity and dysregulated extracellular matrix pathways are common phenotypes in midbrain neurons derived from sporadic and mutation-associated Parkinson's disease patients

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Abstract

Several mutations that cause Parkinsons disease (PD) have been identified over the past decade. These account for 15-25% of PD cases; the rest of the cases are considered sporadic. Currently, it is accepted that PD is not a single monolithic disease but rather a constellation of diseases with some common phenotypes. While rodent models exist for some of the PD-causing mutations, research on the sporadic forms of PD is lagging due to a lack of cellular models. In our study, we differentiated PD patient-derived dopaminergic (DA) neurons from induced pluripotent stem cells (iPSCs) of several PD-causing mutations as well as from sporadic PD patients. Strikingly, we observed a common neurophysiological phenotype: Neurons derived from PD patients had a severe reduction in the rate of synaptic currents compared to those derived from healthy controls. While the relationship between mutations in genes such as the SNCA and LRRK2 and a reduction in synaptic transmission has been investigated before, here we show evidence that the pathogenesis of the synapses in neurons is a general phenotype in PD. Analysis of RNA sequencing results displayed changes in gene expression in different synaptic mechanisms as well as other affected pathways such as extracellular matrix-related pathways. Some of these dysregulated pathways are common to all PD patients (monogenic or idiopathic). Our data, therefore, shows changes that are central and convergent to PD and suggests a strong involvement of the tetra-partite synapse in PD pathophysiology.

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Stern, S., Lau, S., Manole, A., Rosh, I., Percia, M., Ben-Ezer, R., Shokhirev, M., Qiu, F., Schafer, S., Mansour, A., Stern, T., Ofer, P., Stern, Y., Diniz, A. M., Moore, L. R., Nayak, R., Aicher, A., Rhee, A., Wong, T., Nguyen, T., Linker, S. B., Winner, B., Freitas, B., Jones, E., Bardy, C., Brice, A., Winkler, J., Marchetto, M. C., Gage, F. H.. 2022-01-02. Reduced synaptic activity and dysregulated extracellular matrix pathways are common phenotypes in midbrain neurons derived from sporadic and mutation-associated Parkinson's disease patients. https://doi.org/10.1101/2021.12.31.474654

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