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Stern, Shani; Lau, Shong; Manole, Andreea; Rosh, Idan; Percia, Menachem Mendel; Ben Ezer, Ran; Shokhirev, Maxim N; Qiu, Fan; Schafer, Simon; Mansour, Abed AlFatah; Mangan, Kile P; Stern, Tchelet; Ofer, Polina; Stern, Yam; Diniz Mendes, Ana Paula; Djamus, Jose; Moore, Lynne Randolph; Nayak, Ritu; Laufer, Sapir Havusha; Aicher, Aidan; Rhee, Amanda; Wong, Thomas L; Nguyen, Thao; Linker, Sara B; Winner, Beate; Freitas, Beatriz C; Jones, Eugenia; Sagi, Irit; Bardy, Cedric; Brice, Alexis; Winkler, Juergen; Marchetto, Maria C; Gage, Fred H
NPJ Parkinson's Disease, 08/2022, Volume: 8, Issue: 1Journal Article
Several mutations that cause Parkinson's 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 the 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, show changes that are central and convergent to PD and suggest a strong involvement of the tetra-partite synapse in PD pathophysiology.
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