title: Rgs6 is required for adult maintenance of dopaminergic neurons in the ventral substantia nigra.
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.
authors.affiliation: Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM) Montréal, Quebec, Canada; Division of Experimental Medicine, McGill University, Montréal, Quebec, Canada.
authors.forename: Panojot
authors.initials: P
authors.lastname: Bifsha
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
authors.forename: Jianqi
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
authors.forename: Rory A
authors.initials: RA
authors.lastname: Fisher
authors.affiliation: Laboratoire de Génétique Moléculaire, Institut de Recherches Cliniques de Montréal (IRCM) Montréal, Quebec, Canada; Division of Experimental Medicine, McGill University, Montréal, Quebec, Canada.
authors.forename: Jacques
authors.initials: J
authors.lastname: Drouin
mesh_terms: D000818:Animals; D059290:Dopaminergic Neurons / Q000502:physiology*; D018398:Homeodomain Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology; D020710:RGS Proteins / Q000502:physiology*; D015398:Signal Transduction; D013378:Substantia Nigra / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D020710:RGS Proteins; C485692:Rgs6 protein, mouse; D014157:Transcription Factors; C433629:homeobox protein PITX3