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Research Articles, Neurobiology of Disease

VGLUT2 Is a Determinant of Dopamine Neuron Resilience in a Rotenone Model of Dopamine Neurodegeneration

Silas A. Buck, Briana R. De Miranda, Ryan W. Logan, Kenneth N. Fish, J. Timothy Greenamyre and Zachary Freyberg
Journal of Neuroscience 2 June 2021, 41 (22) 4937-4947; DOI: https://doi.org/10.1523/JNEUROSCI.2770-20.2021
Silas A. Buck
1Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213
2Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213
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Briana R. De Miranda
3Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15260
4Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, 35294
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Ryan W. Logan
5Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, 02118
6Center for Systems Neurogenetics of Addiction, The Jackson Laboratory, Bar Harbor, Maine, 04609
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Kenneth N. Fish
2Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213
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J. Timothy Greenamyre
3Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15260
7Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania, 15260
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Zachary Freyberg
2Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213
8Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213
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Abstract

Parkinson's disease (PD) is characterized by progressive dopamine (DA) neuron loss in the SNc. In contrast, DA neurons in the VTA are relatively protected from neurodegeneration, but the underlying mechanisms for this resilience remain poorly understood. Recent work suggests that expression of the vesicular glutamate transporter 2 (VGLUT2) selectively impacts midbrain DA neuron vulnerability. We investigated whether altered DA neuron VGLUT2 expression determines neuronal resilience in rats exposed to rotenone, a mitochondrial complex I inhibitor and toxicant model of PD. We discovered that VTA/SNc DA neurons that expressed VGLUT2 are more resilient to rotenone-induced DA neurodegeneration. Surprisingly, the density of neurons with detectable VGLUT2 expression in the VTA and SNc increases in response to rotenone. Furthermore, dopaminergic terminals within the NAc, where the majority of VGLUT2-expressing DA neurons project, exhibit greater resilience compared with DA terminals in the caudate/putamen. More broadly, VGLUT2-expressing terminals are protected throughout the striatum from rotenone-induced degeneration. Together, our data demonstrate that a distinct subpopulation of VGLUT2-expressing DA neurons are relatively protected from rotenone neurotoxicity. Rotenone-induced upregulation of the glutamatergic machinery in VTA and SNc neurons and their projections may be part of a broader neuroprotective mechanism. These findings offer a putative new target for neuronal resilience that can be manipulated to prevent toxicant-induced DA neurodegeneration in PD.

SIGNIFICANCE STATEMENT Environmental exposures to pesticides contribute significantly to pathologic processes that culminate in Parkinson's disease (PD). The pesticide rotenone has been used to generate a PD model that replicates key features of the illness, including dopamine neurodegeneration. To date, longstanding questions remain: are there dopamine neuron subpopulations resilient to rotenone; and if so, what are the molecular determinants of this resilience? Here we show that the subpopulation of midbrain dopaminergic neurons that express the vesicular glutamate transporter 2 (VGLUT2) are more resilient to rotenone-induced neurodegeneration. Rotenone also upregulates VGLUT2 more broadly in the midbrain, suggesting that VGLUT2 expression generally confers increased resilience to rotenone. VGLUT2 may therefore be a new target for boosting neuronal resilience to prevent toxicant-induced DA neurodegeneration in PD.

  • dopamine
  • glutamate
  • neurodegeneration
  • rotenone
  • tyrosine hydroxylase
  • VGLUT2

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The Journal of Neuroscience: 41 (22)
Journal of Neuroscience
Vol. 41, Issue 22
2 Jun 2021
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VGLUT2 Is a Determinant of Dopamine Neuron Resilience in a Rotenone Model of Dopamine Neurodegeneration
Silas A. Buck, Briana R. De Miranda, Ryan W. Logan, Kenneth N. Fish, J. Timothy Greenamyre, Zachary Freyberg
Journal of Neuroscience 2 June 2021, 41 (22) 4937-4947; DOI: 10.1523/JNEUROSCI.2770-20.2021

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VGLUT2 Is a Determinant of Dopamine Neuron Resilience in a Rotenone Model of Dopamine Neurodegeneration
Silas A. Buck, Briana R. De Miranda, Ryan W. Logan, Kenneth N. Fish, J. Timothy Greenamyre, Zachary Freyberg
Journal of Neuroscience 2 June 2021, 41 (22) 4937-4947; DOI: 10.1523/JNEUROSCI.2770-20.2021
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Keywords

  • dopamine
  • glutamate
  • neurodegeneration
  • rotenone
  • tyrosine hydroxylase
  • VGLUT2

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