Title

The longitudinal transcriptomic response of the substantia nigra to intrastriatal 6-hydroxydopamine reveals significant upregulation of regeneration-associated genes

Authors

Nicholas M. Kanaan, Department of Translational Science & Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America; Morris. K. Udall Center of Excellence in Parkinson's Disease Research, Michigan State University, Grand Rapids, MI, United States of America; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan, United States of America.
Timothy J. Collier, Department of Translational Science & Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America; Morris. K. Udall Center of Excellence in Parkinson's Disease Research, Michigan State University, Grand Rapids, MI, United States of America; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan, United States of America.
Allyson Cole-Strauss, Department of Translational Science & Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America; Morris. K. Udall Center of Excellence in Parkinson's Disease Research, Michigan State University, Grand Rapids, MI, United States of America.
Tessa Grabinski, Department of Translational Science & Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America.
Zachary R. Mattingly, Department of Translational Science & Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America.
Mary E. Winn, Bioinformatics & Biostatistics Core, Van Andel Research Institute, Grand Rapids, MI, United States of America.
Kathy Steece-Collier, Department of Translational Science & Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America; Morris. K. Udall Center of Excellence in Parkinson's Disease Research, Michigan State University, Grand Rapids, MI, United States of America; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan, United States of America.
Caryl E. Sortwell, Department of Translational Science & Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America; Morris. K. Udall Center of Excellence in Parkinson's Disease Research, Michigan State University, Grand Rapids, MI, United States of America; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan, United States of America.
Fredric P. Manfredsson, Department of Translational Science & Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America.
Jack W. Lipton, Department of Translational Science & Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States of America; Morris. K. Udall Center of Excellence in Parkinson's Disease Research, Michigan State University, Grand Rapids, MI, United States of America; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, Grand Rapids, Michigan, United States of America.

Document Type

Article

Abstract

We hypothesized that the study of gene expression at 1, 2, 4, 6 and 16 weeks in the substantia nigra (SN) after intrastriatal 6-OHDA in the Sprague-Dawley rat (rattus norvegicus) would identify cellular responses during the degenerative process that could be axoprotective. Specifically, we hypothesized that genes expressed within the SN that followed a profile of being highly upregulated early after the lesion (during active axonal degeneration) and then progressively declined to baseline over 16 weeks as DA neurons died are indicative of potential protective responses to the striatal 6-OHDA insult. Utilizing a κ-means cluster analysis strategy, we demonstrated that one such cluster followed this hypothesized expression pattern over time, and that this cluster contained several interrelated transcripts that are classified as regeneration-associated genes (RAGs) including Atf3, Sprr1a, Ecel1, Gadd45a, Gpnmb, Sox11, Mmp19, Srgap1, Rab15,Lifr, Trib3, Tgfb1, and Sema3c. All exemplar transcripts tested from this cluster (Sprr1a, Ecel1, Gadd45a, Atf3 and Sox11) were validated by qPCR and a smaller subset (Sprr1a, Gadd45a and Sox11) were shown to be exclusively localized to SN DA neurons using a dual label approach with RNAScope in situ hybridization and immunohistochemistry. Upregulation of RAGs is typically associated with the response to axonal injury in the peripheral nerves and was not previously reported as part of the axodegenerative process for DA neurons of the SN. Interestingly, as part of this cluster, other transcripts were identified based on their expression pattern but without a RAG provenance in the literature. These "RAG-like" transcripts need further characterization to determine if they possess similar functions to or interact with known RAG transcripts. Ultimately, it is hoped that some of the newly identified axodegeneration-reactive transcripts could be exploited as axoprotective therapies in PD and other neurodegenerative diseases.

Medical Subject Headings

Animals; Cluster Analysis; Corpus Striatum (metabolism, pathology); Gene Regulatory Networks; Male; Nerve Regeneration (genetics); Oxidopamine; RNA, Messenger (genetics, metabolism); Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Reproducibility of Results; Signal Transduction (genetics); Substantia Nigra (metabolism); Transcriptome (genetics); Up-Regulation (genetics)

Publication Date

1-1-2015

Publication Title

PloS one

E-ISSN

1932-6203

Volume

10

Issue

5

First Page

e0127768

PubMed ID

25992874

Digital Object Identifier (DOI)

10.1371/journal.pone.0127768

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