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

Panojot Bifsha; Jianqi Yang; Rory A Fisher; Jacques Drouin

doi:10.1371/journal.pgen.1004863

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

Journal article

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

Panojot Bifsha, Jianqi Yang, Rory A Fisher and Jacques Drouin

PLoS genetics, Vol.10(12), pp.e1004863-e1004863

12/2014

DOI: 10.1371/journal.pgen.1004863

PMCID: PMC4263397

PMID: 25501001

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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.

Transcription Factors - metabolism

Parkinson Disease - pathology

Animals

Signal Transduction

Substantia Nigra - pathology

Homeodomain Proteins - metabolism

Mice, Inbred C57BL

Dopaminergic Neurons - physiology

RGS Proteins - physiology

Parkinson Disease - genetics

Organ Specificity

Mice, Knockout

Details

Title: Subtitle: Rgs6 is required for adult maintenance of dopaminergic neurons in the ventral substantia nigra
Creators: Panojot Bifsha - Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM) Montréal, Quebec, Canada; Division of Experimental Medicine, McGill University, Montréal, Quebec, Canada
Jianqi Yang - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America
Rory A Fisher - Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America
Jacques Drouin - Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM) Montréal, Quebec, Canada; Division of Experimental Medicine, McGill University, Montréal, Quebec, Canada
Resource Type: Journal article
Publication Details: PLoS genetics, Vol.10(12), pp.e1004863-e1004863
DOI: 10.1371/journal.pgen.1004863
PMID: 25501001
PMCID: PMC4263397
NLM abbreviation: PLoS Genet
ISSN: 1553-7390
eISSN: 1553-7404
Publisher: Public Library Science; United States
Grant note: MOP-123213 / Canadian Institutes of Health Research CA161882 / NCI NIH HHS R01 CA161882 / NCI NIH HHS
Language: English
Date published: 12/2014
Academic Unit: Iowa Neuroscience Institute; Neuroscience and Pharmacology; Internal Medicine
Record Identifier: 9984040016302771

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