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Journal article
Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson’s disease patients
NPJ Parkinson's Disease, Vol.8(1), 103
10/Aug/2022
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.
Details
- Title
- Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson’s disease patients
- Creators
- Shani Stern (Corresponding Author) - Salk Institute for Biological StudiesShong Lau - Salk Institute for Biological StudiesAndreea Manole - Salk Institute for Biological StudiesIdan Rosh - University of HaifaMenachem Mendel Percia - University of HaifaRan Ben Ezer - University of HaifaMaxim N. Shokhirev - Salk Institute for Biological StudiesFan Qiu - Salk Institute for Biological StudiesSimon Schafer - Salk Institute for Biological StudiesAbed AlFatah Mansour - Salk Institute for Biological StudiesKile P. Mangan - FujifilmTchelet Stern - Salk Institute for Biological StudiesPolina Ofer - Salk Institute for Biological StudiesYam Stern - Salk Institute for Biological StudiesAna Paula Diniz Mendes - Salk Institute for Biological StudiesJose Djamus - University of HaifaLynne Randolph Moore - Salk Institute for Biological StudiesRitu Nayak - University of HaifaAidan Aicher - Salk Institute for Biological StudiesSapir Havusha Laufer - 972WIS_INST___120Amanda Rhee - Salk Institute for Biological StudiesThomas L. Wong - Salk Institute for Biological StudiesThao Nguyen - Salk Institute for Biological StudiesSara B. Linker - Salk Institute for Biological StudiesBeate Winner - Friedrich-Alexander-Universität Erlangen-NürnbergBeatriz C. Freitas - FujifilmEugenia Jones - FujifilmIrit Sagi - 972WIS_INST___120Cedric Bardy - South Australian Health and Medical Research InstituteAlexis Brice - Institut du CerveauJuergen Winkler - Friedrich-Alexander-Universität Erlangen-NürnbergMaria C. Marchetto - University of California, San DiegoFred H. Gage (Corresponding Author) - Salk Institute for Biological Studies
- Resource Type
- Journal article
- Publication Details
- NPJ Parkinson's Disease, Vol.8(1), 103; 10/Aug/2022
- Number of pages
- 16
- Publisher
- Nature Portfolio
- Language
- English
- DOI
- https://doi.org/10.1038/s41531-022-00366-z
- Grant note
- The authors would like to thank K.E. Diffenderfer for technical assistance and M.L. Gage for editorial comments. They would also like to acknowledge the Salk Institute Stem Cell Core, Waitt Biophotonics Core, and Next Generation Sequencing Core for technical support. Funding to the cores provided in part by NIH-NCI CCSG: P30 014195. This work was supported by the JPB Foundation, American Heart Association/Paul G. Allen Frontiers Group Brain Health & Cognitive Impairment Initiative (19PABHI34610000), The Milky Way Research Foundation, Annette C. Merle-Smith and the G. Harold and Leila Y. Mathers Charitable Foundation, NIH AG056306 to F.H.G., NIH R01AG056411-02 to C.K.G., NIH DP5OD023071-03 to J.R.D., Zuckerman STEM leadership program and ISF 1994/21 to S.S. Alzheimer's Association Research Fellowship (AARF) Program (A.M.), Bavarian Ministry of Science and the Arts in the framework of the ForInter network (J.W. and B.W.), Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) WI 3567/2-1 (B.W.), The Michael J Fox Foundation, The Shake It Up Foundation Australia, The Hospital Research Foundation: Parkinson’s South Australia, The Grosset Gaia Foundation, Michael and Angelique Boileau Corporate Philanthropy to C.B., EMBO Postdoctoral Long-term Fellowship (ALTF 1214-2014) and Human Frontiers Science Program (HFSP Long-Term Fellowship- LT001074/2015) for A.A.M. S.S. differentiated neurons, did patch clamp experiments, performed data analysis, design of experiments, and manuscript writing, S.L. differentiated neurons and prepared RNA, A.M. performed immunohistochemistry (IHC), imaging of aggregated proteins, M.P. differentiated neurons and performed IHC, I.R. differentiated neurons and performed IHC, M.P. performed ICC experiments, R.B.R., M.N.S., R.N.A., F.Q., S.S., and S.B.L. performed RNA sequencing analysis, A.A.M. performed IHC, K.M. performed MEA experiments, TS performed confocal imaging and quantification, P.O. differentiated neurons, Y.S. performed confocal imaging, A.M.D. grew cells, J.D. performed electrophysiological recordings analysis, L.R.M. prepared lenti-virus, R.N. differentiated neurons, S.K. helped with the ECM experiments, A.A. performed quantification of images, A.R. and T.L.W. performed quantification of aggresome images, T.N. differentiated neurons, B.W. reprogrammed fibroblasts into iPSCs, B.C.F. differentiated neurons, E.J. helped with the design of experiments, I.S. helped with the ECM experiments, C.B. performed path clamp experiments, A.B. and J.W. diagnosed patients, M.C.M. differentiated neurons and helped with design of experiments, F.H.G. designed research and manuscript writing.
- Record Identifier
- 993395480303596
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