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Rgs6 is required for adult maintenance of dopaminergic neurons in the ventral substantia nigra.

Bifsha P, Yang J, Fisher RA, Drouin J - PLoS Genet. (2014)

Bottom Line: Unilateral cell loss is accompanied by contralateral degenerating neurons that exhibit smaller cell size, altered morphology and reduced dendritic network.The degenerating neurons have low levels of tyrosine hydroxylase (TH) and decreased nuclear Pitx3; accordingly, expression of many Pitx3 target gene products is altered, including Vmat2, Bdnf, Aldh1a1 (Adh2) and Fgf10.Rgs6-dependent protection is thus critical for adult survival and maintenance of the vSNc mDA neurons that are most affected in PD.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM) Montréal, Quebec, Canada; Division of Experimental Medicine, McGill University, Montréal, Quebec, Canada.

ABSTRACT
Parkinson disease (PD) is characterized by the preferential, but poorly understood, vulnerability to degeneration of midbrain dopaminergic (mDA) neurons in the ventral substantia nigra compacta (vSNc). These sensitive mDA neurons express Pitx3, a transcription factor that is critical for their survival during development. We used this dependence to identify, by flow cytometry and expression profiling, the negative regulator of G-protein signaling Rgs6 for its restricted expression in these neurons. In contrast to Pitx3-/- mDA neurons that die during fetal (vSNc) or post-natal (VTA) period, the vSNc mDA neurons of Rgs6-/- mutant mice begin to exhibit unilateral signs of degeneration at around 6 months of age, and by one year cell loss is observed in a fraction of mice. Unilateral cell loss is accompanied by contralateral degenerating neurons that exhibit smaller cell size, altered morphology and reduced dendritic network. The degenerating neurons have low levels of tyrosine hydroxylase (TH) and decreased nuclear Pitx3; accordingly, expression of many Pitx3 target gene products is altered, including Vmat2, Bdnf, Aldh1a1 (Adh2) and Fgf10. These low TH neurons also express markers of increased dopamine signaling, namely increased DAT and phospho-Erk1/2 expression. The late onset degeneration may reflect the protective action of Rgs6 against excessive DA signaling throughout life. Rgs6-dependent protection is thus critical for adult survival and maintenance of the vSNc mDA neurons that are most affected in PD.

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Rgs6−/− mice as a model for Parkinsonian neurodegeneration.(A) Rgs6-dependent signaling pathways in vSNc mDA neurons control Pitx3 expression, which itself controls expression of Aldh1a1, TH, Fgf10, Vmat2 and Bdnf. Together, Rgs6 and Pitx3 define a survival pathway in these neurons. The dopamine receptor Drd2 may be a target of Rgs6 action and consistent with this hypothesis, expression of the dopamine transporter DAT is up-regulated in Rgs6−/− vSNc. (B) Schematic representation of major subsets of SNc mDA neurons present at different ages in midbrains of Rgs6−/− mice showing progressive degeneration (small pale green) followed by loss of vSNc mDA neurons.
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pgen-1004863-g009: Rgs6−/− mice as a model for Parkinsonian neurodegeneration.(A) Rgs6-dependent signaling pathways in vSNc mDA neurons control Pitx3 expression, which itself controls expression of Aldh1a1, TH, Fgf10, Vmat2 and Bdnf. Together, Rgs6 and Pitx3 define a survival pathway in these neurons. The dopamine receptor Drd2 may be a target of Rgs6 action and consistent with this hypothesis, expression of the dopamine transporter DAT is up-regulated in Rgs6−/− vSNc. (B) Schematic representation of major subsets of SNc mDA neurons present at different ages in midbrains of Rgs6−/− mice showing progressive degeneration (small pale green) followed by loss of vSNc mDA neurons.

Mentions: The regulatory action of Rgs6 was associated with various GPCRs, in particular the dopamine receptor D2 (Drd2) [25]. Ventral SNc mDA neurons are subject to regulatory negative feedback mediated by Drd2 autoreceptors. Expression of Drd2 itself is not affected in vSNc mDA neurons of Rgs6−/− mice (Fig. 8A) despite its dependence on Pitx3 [19]. Dopamine signalling in these neurons leads to activation of Erk1/2 [41] and accordingly, we observed significant phospho-Erk1/2 only in THlow neurons of Rgs6−/− vSNc (Fig. 8B). In addition, enhanced DA signalling downstream of Drd2 [42] would be expected to increase expression of the dopamine transporter DAT (SLC6A3) which is otherwise dependent on Pitx3. It was indeed observed that activated glycosyl-DAT is high in THlow neurons of Rgs6−/− vSNC (Fig. 8C). Thus, high DAT would presumably increase intracellular DA levels in these neurons by promoting DA uptake [43]. Cytoplasmic DA would be further enhanced by the decrease of Pitx3-dependent [43] Vmat2 (Fig. 7B) which is responsible for sequestration of DA into vesicles. Thus, the combined elevation of DAT with decreased Vmat2 is very likely to maintain high levels of free DA that may be toxic [44] and contribute to the degenerative process and cell death [45]. Increased DA signalling thus constitutes a putative mechanism to explain the late-onset neurodegeneration observed in Rgs6−/− vSNc mDA neurons (Fig. 9A).


Rgs6 is required for adult maintenance of dopaminergic neurons in the ventral substantia nigra.

Bifsha P, Yang J, Fisher RA, Drouin J - PLoS Genet. (2014)

Rgs6−/− mice as a model for Parkinsonian neurodegeneration.(A) Rgs6-dependent signaling pathways in vSNc mDA neurons control Pitx3 expression, which itself controls expression of Aldh1a1, TH, Fgf10, Vmat2 and Bdnf. Together, Rgs6 and Pitx3 define a survival pathway in these neurons. The dopamine receptor Drd2 may be a target of Rgs6 action and consistent with this hypothesis, expression of the dopamine transporter DAT is up-regulated in Rgs6−/− vSNc. (B) Schematic representation of major subsets of SNc mDA neurons present at different ages in midbrains of Rgs6−/− mice showing progressive degeneration (small pale green) followed by loss of vSNc mDA neurons.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263397&req=5

pgen-1004863-g009: Rgs6−/− mice as a model for Parkinsonian neurodegeneration.(A) Rgs6-dependent signaling pathways in vSNc mDA neurons control Pitx3 expression, which itself controls expression of Aldh1a1, TH, Fgf10, Vmat2 and Bdnf. Together, Rgs6 and Pitx3 define a survival pathway in these neurons. The dopamine receptor Drd2 may be a target of Rgs6 action and consistent with this hypothesis, expression of the dopamine transporter DAT is up-regulated in Rgs6−/− vSNc. (B) Schematic representation of major subsets of SNc mDA neurons present at different ages in midbrains of Rgs6−/− mice showing progressive degeneration (small pale green) followed by loss of vSNc mDA neurons.
Mentions: The regulatory action of Rgs6 was associated with various GPCRs, in particular the dopamine receptor D2 (Drd2) [25]. Ventral SNc mDA neurons are subject to regulatory negative feedback mediated by Drd2 autoreceptors. Expression of Drd2 itself is not affected in vSNc mDA neurons of Rgs6−/− mice (Fig. 8A) despite its dependence on Pitx3 [19]. Dopamine signalling in these neurons leads to activation of Erk1/2 [41] and accordingly, we observed significant phospho-Erk1/2 only in THlow neurons of Rgs6−/− vSNc (Fig. 8B). In addition, enhanced DA signalling downstream of Drd2 [42] would be expected to increase expression of the dopamine transporter DAT (SLC6A3) which is otherwise dependent on Pitx3. It was indeed observed that activated glycosyl-DAT is high in THlow neurons of Rgs6−/− vSNC (Fig. 8C). Thus, high DAT would presumably increase intracellular DA levels in these neurons by promoting DA uptake [43]. Cytoplasmic DA would be further enhanced by the decrease of Pitx3-dependent [43] Vmat2 (Fig. 7B) which is responsible for sequestration of DA into vesicles. Thus, the combined elevation of DAT with decreased Vmat2 is very likely to maintain high levels of free DA that may be toxic [44] and contribute to the degenerative process and cell death [45]. Increased DA signalling thus constitutes a putative mechanism to explain the late-onset neurodegeneration observed in Rgs6−/− vSNc mDA neurons (Fig. 9A).

Bottom Line: Unilateral cell loss is accompanied by contralateral degenerating neurons that exhibit smaller cell size, altered morphology and reduced dendritic network.The degenerating neurons have low levels of tyrosine hydroxylase (TH) and decreased nuclear Pitx3; accordingly, expression of many Pitx3 target gene products is altered, including Vmat2, Bdnf, Aldh1a1 (Adh2) and Fgf10.Rgs6-dependent protection is thus critical for adult survival and maintenance of the vSNc mDA neurons that are most affected in PD.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM) Montréal, Quebec, Canada; Division of Experimental Medicine, McGill University, Montréal, Quebec, Canada.

ABSTRACT
Parkinson disease (PD) is characterized by the preferential, but poorly understood, vulnerability to degeneration of midbrain dopaminergic (mDA) neurons in the ventral substantia nigra compacta (vSNc). These sensitive mDA neurons express Pitx3, a transcription factor that is critical for their survival during development. We used this dependence to identify, by flow cytometry and expression profiling, the negative regulator of G-protein signaling Rgs6 for its restricted expression in these neurons. In contrast to Pitx3-/- mDA neurons that die during fetal (vSNc) or post-natal (VTA) period, the vSNc mDA neurons of Rgs6-/- mutant mice begin to exhibit unilateral signs of degeneration at around 6 months of age, and by one year cell loss is observed in a fraction of mice. Unilateral cell loss is accompanied by contralateral degenerating neurons that exhibit smaller cell size, altered morphology and reduced dendritic network. The degenerating neurons have low levels of tyrosine hydroxylase (TH) and decreased nuclear Pitx3; accordingly, expression of many Pitx3 target gene products is altered, including Vmat2, Bdnf, Aldh1a1 (Adh2) and Fgf10. These low TH neurons also express markers of increased dopamine signaling, namely increased DAT and phospho-Erk1/2 expression. The late onset degeneration may reflect the protective action of Rgs6 against excessive DA signaling throughout life. Rgs6-dependent protection is thus critical for adult survival and maintenance of the vSNc mDA neurons that are most affected in PD.

Show MeSH
Related in: MedlinePlus