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

Panojot Bifsha,Rory A Fisher,Jianqi Yang,Jacques Drouin,Gregory P Copenhaver

doi:10.1371/journal.pgen.1004863

Panojot Bifsha, Rory A Fisher + Show 3 more

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https://doi.org/10.1371/journal.pgen.1004863

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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.

Highlights

Parkinson disease (PD) is characterised by the progressive loss of midbrain dopaminergic neurons [1]
The etiology of PD appears to be multifactorial but one consistent feature of this disease is the greater sensitivity of ventral substantia nigra compacta midbrain dopaminergic (mDA) neurons to degenerate [2] as opposed to mDA neurons of the dorsal SNc and ventral tegmental area (VTA)
Unbiased clustering of the 1813 differentially expressed genes into seven clusters defined genes that are expressed in specific subsets of mDA neurons and/or that are Pitx3-dependent in VTA (Fig. 2A). quantitative real-time PCR (qRT-PCR) analyses confirmed the expected enrichment for ventral substantia nigra compacta (vSNc) (Girk2, DAT), dorsal SNc (dSNc) (Calb1) and VTA (Otx2, Calb1) markers (Fig. 2B)

Summary

Introduction

Parkinson disease (PD) is characterised by the progressive loss of midbrain dopaminergic (mDA) neurons [1]. It is noteworthy that rat models of Pink and DJ-1 lossof-function showed progressive loss of mDA neurons [8]. Both early-onset and late-onset forms of PD bear a major histopathological hallmark, the presence of Lewy bodies, which are asynuclein-rich protein inclusions that are found in nondopaminergic brain regions depending on the stage of disease progression. Many familial PD genes have widespread brain expression, without any preferential expression in mDA subpopulations [5] They all participate in similar inter-related cellular processes such as in mitochondrial function (PINK1, DJ-1, SNCA), the secretory pathway (PARK2, LRRK2) and the ubiquitin-proteasome degradation pathway (PINK1, SNCA, PARK2)

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