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ORIGINAL RESEARCH article

Front. Cell. Neurosci.
Sec. Cellular Neurophysiology
Volume 18 - 2024 | doi: 10.3389/fncel.2024.1477511

Translational profiling reveals novel gene expression changes in the direct and indirect pathways in a mouse model of Levodopa induced dyskinesia

Provisionally accepted
Sabika Jafri Sabika Jafri 1Mahdi Ghani Mahdi Ghani 2Natalie Stickle Natalie Stickle 3Carl Virtanen Carl Virtanen 3Lili-Naz Hazrati Lili-Naz Hazrati 4Naomi P Visanji Naomi P Visanji 1,2,5*
  • 1 Krembil Brain Institute, University Health Network (UHN), Toronto, Ontario, Canada
  • 2 Tanz Centre for Research on Neurodegenerative Diseases, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
  • 3 University Health Network (UHN), Toronto, Ontario, Canada
  • 4 Department of Pathology, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
  • 5 Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

The final, formatted version of the article will be published soon.

    The molecular mechanisms underlying L-dihydroxyphenylalanine (LDOPA) induced dyskinesia in Parkinson's disease are poorly understood. Here we employ two transgenic mouse lines, combining translating ribosomal affinity purification (TRAP) with bacterial artificial chromosome expression (Bac), to selectively isolate RNA from either DRD1A expressing striatonigral, or DRD2 expressing striatopallidal medium spiny neurons (MSNs) of the direct and indirect pathways respectively, to study changes in translational gene expression following repeated LDOPA treatment. 6-OHDA lesioned DRD1A and DRD2 BacTRAP mice were treated with either saline or LDOPA bi-daily for 21 days over which time they developed abnormal involuntary movements reminiscent of dyskinesia. On day 22, all animals received LDOPA 40 minutes prior to sacrifice. The striatum of the lesioned hemisphere was dissected and subject to TRAP. Extracted ribosomal RNA was amplified, purified and gene expression was quantified using microarray. 195 significantly varying transcripts were identified among the 4 treatment groups. Pathway analysis revealed an overrepresentation of calcium signaling and long-term potentiation in the DRD1A expressing MSNs of the direct pathway, with significant involvement of long-term depression in the DRD2 expressing MSNs of the indirect pathway following chronic treatment with LDOPA. Several MAPK associated genes (NR4A1, GADD45G, STMN1, FOS and DUSP1) differentiated the direct and indirect pathways following both acute and chronic LDOPA treatment. However, the MAPK pathway activator PAK1 was downregulated in the indirect pathway and upregulated in the direct pathway, strongly suggesting a role for PAK1 in regulating the opposing effects of LDOPA on these two pathways in dyskinesia. Future studies will assess the potential of targeting these genes and pathways to prevent the development of LDOPA-induced dyskinesia.

    Keywords: Parkinson's disease, Levodopa, Dyskinesia, Gene Expression, MAPK pathway

    Received: 07 Aug 2024; Accepted: 18 Nov 2024.

    Copyright: © 2024 Jafri, Ghani, Stickle, Virtanen, Hazrati and Visanji. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Naomi P Visanji, Krembil Brain Institute, University Health Network (UHN), Toronto, M5G 2C4, Ontario, Canada

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.