Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson’s disease patients

Shani Stern, Shong Lau, Andreea Manole, Idan Rosh, Menachem Mendel Percia, Ran Ben Ezer, Maxim N. Shokhirev, Fan Qiu, Simon Schafer, Abed Al Fatah Mansour, Kile P. Mangan, Tchelet Stern, Polina Ofer, Yam Stern, Ana Paula Diniz Mendes, Jose Djamus, Lynne Randolph Moore, Ritu Nayak, Sapir Havusha Laufer, Aidan AicherAmanda Rhee, Thomas L. Wong, Thao Nguyen, Sara B. Linker, Beate Winner, Beatriz C. Freitas, Eugenia Jones, Irit Sagi, Cedric Bardy, Alexis Brice, Juergen Winkler, Maria C. Marchetto, Fred H. Gage

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number103
Journalnpj Parkinson's Disease
Volume8
Issue number1
DOIs
Publication statusPublished or Issued - Dec 2022

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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