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 Aicher; Amanda 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

doi:10.1038/s41531-022-00366-z

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^*

^*Corresponding author for this work

Department of Medical Neurobiology

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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 language	American English
Article number	103
Journal	npj Parkinson's Disease
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41531-022-00366-z
State	Published - Dec 2022

Bibliographical note

Funding Information:
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.

Funding Information:
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.

Publisher Copyright:
© 2022, The Author(s).

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Stern, S., Lau, S., Manole, A., Rosh, I., Percia, M. M., Ben Ezer, R., Shokhirev, M. N., Qiu, F., Schafer, S., Mansour, A. A. F., Mangan, K. P., Stern, T., Ofer, P., Stern, Y., Diniz Mendes, A. P., Djamus, J., Moore, L. R., Nayak, R., Laufer, S. H., ... Gage, F. H. (2022). Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson’s disease patients. npj Parkinson's Disease, 8(1), Article 103. https://doi.org/10.1038/s41531-022-00366-z

@article{e2e5d122266b4644af65ad50503459f3,

title = "Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson{\textquoteright}s disease patients",

abstract = "Several mutations that cause Parkinson{\textquoteright}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.",

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

note = "Funding Information: 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{\textquoteright}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. Funding Information: 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{\textquoteright}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. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s41531-022-00366-z",

language = "American English",

volume = "8",

journal = "npj Parkinson's Disease",

issn = "2373-8057",

publisher = "Springer Nature",

number = "1",

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Stern, S, Lau, S, Manole, A, Rosh, I, Percia, MM, Ben Ezer, R, Shokhirev, MN, Qiu, F, Schafer, S, Mansour, AAF, Mangan, KP, Stern, T, Ofer, P, Stern, Y, Diniz Mendes, AP, Djamus, J, Moore, LR, Nayak, R, Laufer, SH, Aicher, A, Rhee, A, Wong, TL, Nguyen, T, Linker, SB, Winner, B, Freitas, BC, Jones, E, Sagi, I, Bardy, C, Brice, A, Winkler, J, Marchetto, MC & Gage, FH 2022, 'Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson’s disease patients', npj Parkinson's Disease, vol. 8, no. 1, 103. https://doi.org/10.1038/s41531-022-00366-z

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 - Funding Information: 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. Funding Information: 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. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

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.

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ER -

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

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