TY - JOUR
T1 - Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson’s disease patients
AU - Stern, Shani
AU - Lau, Shong
AU - Manole, Andreea
AU - Rosh, Idan
AU - Percia, Menachem Mendel
AU - Ben Ezer, Ran
AU - Shokhirev, Maxim N.
AU - Qiu, Fan
AU - Schafer, Simon
AU - Mansour, Abed Al Fatah
AU - Mangan, Kile P.
AU - Stern, Tchelet
AU - Ofer, Polina
AU - Stern, Yam
AU - Diniz Mendes, Ana Paula
AU - Djamus, Jose
AU - Moore, Lynne Randolph
AU - Nayak, Ritu
AU - Laufer, Sapir Havusha
AU - Aicher, Aidan
AU - Rhee, Amanda
AU - Wong, Thomas L.
AU - Nguyen, Thao
AU - Linker, Sara B.
AU - Winner, Beate
AU - Freitas, Beatriz C.
AU - Jones, Eugenia
AU - Sagi, Irit
AU - Bardy, Cedric
AU - Brice, Alexis
AU - Winkler, Juergen
AU - Marchetto, Maria C.
AU - Gage, Fred H.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/8/10
Y1 - 2022/8/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85135853844&partnerID=8YFLogxK
U2 - 10.1038/s41531-022-00366-z
DO - 10.1038/s41531-022-00366-z
M3 - Article
C2 - 35948563
AN - SCOPUS:85135853844
SN - 2373-8057
VL - 8
JO - npj Parkinson's Disease
JF - npj Parkinson's Disease
IS - 1
M1 - 103
ER -