Druggable transcriptomic pathways revealed in Parkinson’s patient-derived midbrain neurons

Mark van den Hurk, Shong Lau, Maria C. Marchetto, Jerome Mertens, Shani Stern, Olga Corti, Alexis Brice, Beate Winner, Jürgen Winkler, Fred H. Gage, Cedric Bardy

Research output: Contribution to journalArticlepeer-review

Abstract

Complex genetic predispositions accelerate the chronic degeneration of midbrain substantia nigra neurons in Parkinson’s disease (PD). Deciphering the human molecular makeup of PD pathophysiology can guide the discovery of therapeutics to slow the disease progression. However, insights from human postmortem brain studies only portray the latter stages of PD, and there is a lack of data surrounding molecular events preceding the neuronal loss in patients. We address this gap by identifying the gene dysregulation of live midbrain neurons reprogrammed in vitro from the skin cells of 42 individuals, including sporadic and familial PD patients and matched healthy controls. To minimize bias resulting from neuronal reprogramming and RNA-seq methods, we developed an analysis pipeline integrating PD transcriptomes from different RNA-seq datasets (unsorted and sorted bulk vs. single-cell and Patch-seq) and reprogramming strategies (induced pluripotency vs. direct conversion). This PD cohort’s transcriptome is enriched for human genes associated with known clinical phenotypes of PD, regulation of locomotion, bradykinesia and rigidity. Dysregulated gene expression emerges strongest in pathways underlying synaptic transmission, metabolism, intracellular trafficking, neural morphogenesis and cellular stress/immune responses. We confirmed a synaptic impairment with patch-clamping and identified pesticides and endoplasmic reticulum stressors as the most significant gene-chemical interactions in PD. Subsequently, we associated the PD transcriptomic profile with candidate pharmaceuticals in a large database and a registry of current clinical trials. This study highlights human transcriptomic pathways that can be targeted therapeutically before the irreversible neuronal loss. Furthermore, it demonstrates the preclinical relevance of unbiased large transcriptomic assays of reprogrammed patient neurons.

Original languageEnglish
Article number134
Pages (from-to)134
Journalnpj Parkinson's Disease
Volume8
Issue number1
DOIs
StatePublished - 18 Oct 2022

Bibliographical note

Funding Information:
We thank Clive Svendsen, Ritchie Ho and Alexander Laperle for kindly supplying helpful information to support the analysis, along with access to raw sequencing data for the Bulk-iPS-Mixed dataset and Hugo Fernandes, Nikolai’s Patikas, Emmanouil Metzakopian and colleagues for providing providing access to raw sequencing data for the sc-iPS-10Xseq dataset. We thank Ben Lewis and M.L. Gage for editorial comments. We thank the DNA and cell bank of the Institut du Cerveau for some of the human samples preparation. We are grateful for the generous support from The Flinders Foundation (CB), The Australian Medical Research Future Fund (CB), Rebecca L Cooper Foundation (CB), the Neurological Research Foundation (CB), The Boileau Family (CB), The Grosset Gaia Fund (CB), The Hospital Research Foundation Parkinson’s SA (CB), The Shake it Up Foundation (CB), Michael J Fox Foundation (CB). Additional support came from The AHA-Allen Initiative award 19PABH134610000 (FHG), the Paul G. Allen Family Foundation (FHG), the NIA R01s AG056306 (FHG), AG056511 (FHG), and AG057706 (FHG), the JPB Foundation (FHG), and the Ray and Dagmar Dolby Family Fund (FHG); the Netherlands Organisation for Scientific Research (NWO) Rubicon Fellowship 019.163LW.032 (MvdH); Zuckerman STEM leadership program (SS); the Bavarian Ministry of Science and the Arts in the framework of the ForInter network (BW, JW), the German Research Foundation, DFG WI 3567/2-1 (BW) and 270949263/GRK2162 (BW, JW) and the IZKF advanced project E30 (BW, JW).

Funding Information:
We thank Clive Svendsen, Ritchie Ho and Alexander Laperle for kindly supplying helpful information to support the analysis, along with access to raw sequencing data for the Bulk-iPS-Mixed dataset and Hugo Fernandes, Nikolai’s Patikas, Emmanouil Metzakopian and colleagues for providing providing access to raw sequencing data for the sc-iPS-10Xseq dataset. We thank Ben Lewis and M.L. Gage for editorial comments. We thank the DNA and cell bank of the Institut du Cerveau for some of the human samples preparation. We are grateful for the generous support from The Flinders Foundation (CB), The Australian Medical Research Future Fund (CB), Rebecca L Cooper Foundation (CB), the Neurological Research Foundation (CB), The Boileau Family (CB), The Grosset Gaia Fund (CB), The Hospital Research Foundation Parkinson’s SA (CB), The Shake it Up Foundation (CB), Michael J Fox Foundation (CB). Additional support came from The AHA-Allen Initiative award 19PABH134610000 (FHG), the Paul G. Allen Family Foundation (FHG), the NIA R01s AG056306 (FHG), AG056511 (FHG), and AG057706 (FHG), the JPB Foundation (FHG), and the Ray and Dagmar Dolby Family Fund (FHG); the Netherlands Organisation for Scientific Research (NWO) Rubicon Fellowship 019.163LW.032 (MvdH); Zuckerman STEM leadership program (SS); the Bavarian Ministry of Science and the Arts in the framework of the ForInter network (BW, JW), the German Research Foundation, DFG WI 3567/2-1 (BW) and 270949263/GRK2162 (BW, JW) and the IZKF advanced project E30 (BW, JW).

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

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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