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

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 ?-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.

SUBMITTER: Kanaan NM

PROVIDER: S-EPMC4439078 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Kanaan Nicholas M NM Collier Timothy J TJ Cole-Strauss Allyson A Grabinski Tessa T Mattingly Zachary R ZR Winn Mary E ME Steece-Collier Kathy K Sortwell Caryl E CE Manfredsson Fredric P FP Lipton Jack W JW

PloS one 20150520 5

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 1 ...[more]

PMID: 25992874

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Project description:IntroductionDespite the widespread use of the unilateral striatal 6-hydroxydopamine (6-OHDA) lesion model in mice in recent years, the stability of behavioral deficits in the 6-OHDA striatal mouse model over time is not yet clear, raising concerns about using this model to evaluate a compound's long-term therapeutic effects.Materials and methodsIn the current study, mice were tested at regular intervals in the cylinder test and gait analysis beginning 3 days after 6-OHDA injection of 4 and 8 μg and lasting until 56 days post-lesion. Apomorphine-induced rotational test and rotarod test were also performed on Day 23 and 43 post-lesion, respectively. Immunohistochemistry for dopaminergic neurons stained by tyrosine hydroxylase (TH) was also performed.ResultsOur results showed that both the 4 and 8 μg 6-OHDA lesion groups exhibited forelimb use asymmetry with a preference for the ipsilateral (injection) side on Day 3 and until Day 21 post-lesion, but did not show forelimb asymmetry on Day 28 to 56 post-lesion. The 8 μg 6-OHDA lesion group still exhibited forelimb asymmetry on Day 28 and 42 post-lesion, but not on Day 56. The gait analysis showed that the contralateral front and hind step cycles increased from Day 3 to 42 post-lesion and recovered on Day 56 post-lesion. In addition, our results displayed a dose-dependent reduction in TH+ cells and TH+ fibers, as well as dose-dependent apomorphine-induced rotations. In the rotarod test, the 8 μg 6-OHDA lesion group, but not the 4 μg group, decreased the latency to fall on the rotarod on Day 43 post-lesion.ConclusionIn summary, unilateral striatal 6-OHDA injections of 4 and 8 μg induced spontaneous motor impairment in mice, which partially recovered starting on Day 28 post-lesion. Forced motor deficits were observed in the 8 g 6-OHDA lesion group, which remained stable on Day 43 post-lesion. In addition, the rotarod test and apomorphine-induced rotational test can distinguish between lesions of different extents and are useful tools for the assessment of functional recovery in studies screening novel potential therapies.

Dataset Information

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

Publications

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

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