Elsevier

Biological Psychiatry

Volume 50, Issue 10, 15 November 2001, Pages 813-816
Biological Psychiatry

Elevated levels of ΔFosB and RGS9 in striatum in Parkinson’s disease

https://doi.org/10.1016/S0006-3223(01)01234-3Get rights and content

Abstract

Introduction: In the present study, we determined whether certain proteins known to mediate dopamine signaling in striatum show abnormal levels in Parkinson’s disease.

Methods: Protein levels were assayed by western blotting in samples of caudate nucleus and putamen obtained at autopsy from patients with Parkinson’s disease and from control subjects. Levels of several markers of dopaminergic function were also assayed.

Results: Levels of the transcription factor ΔFosB and of the G protein modulatory protein RGS9 were both increased in caudate and putamen from patients with Parkinson’s disease. Levels of several other proteins were not affected. Interestingly, levels of both ΔFosB and RGS9 correlated inversely with putamen levels of dopamine, dopamine metabolites, and the dopamine transporter.

Conclusions: These findings are consistent with observations in laboratory animals, which have demonstrated elevated levels of ΔFosB in striatum after denervation of the midbrain dopamine system, and confirm that similar adaptations in ΔFosB and RGS9 occur in humans with Parkinson’s disease. Knowledge of these adaptations can help us understand the changes in striatal function associated with Parkinson’s disease and assist in the development of novel treatments.

Introduction

Parkinson’s disease is characterized by the progressive death of dopaminergic neurons in the midbrain substantia nigra Hornykiewicz and Kish 1987. These neurons project to the caudate nucleus and putamen, which together comprise the dorsal striatum. The gradual decline in the number of nigrostriatal dopaminergic neurons leads to decreases in the overall dopamine content in the striatum. This loss of dopaminergic innervation explains many of the abnormalities in extrapyramidal motor function that characterize Parkinson’s disease; however, our understanding of the molecular adaptations that occur in striatum as a result of denervation of the dopamine system remains incomplete.

In rodents and in nonhuman primates, denervation of midbrain dopamine systems has been shown to cause the induction of ΔFosB in dorsal striatum Hope et al 1994, Doucet et al 1996, Perez-Otano et al 1998, Cenci et al 1999. In the present study, we tested the hypothesis that a similar increase in striatal levels of ΔFosB occurs in Parkinson’s disease. ΔFosB is a novel Fos family transcription factor that is implicated in mediating the long-term effects of dopamine denervation, and several other chronic perturbations, on striatal function (Kelz and Nestler 2000).

We also examined whether levels of RGS9-2 (Regulator of G protein signaling 9-2) are altered in Parkinson’s disease. RGS9-2 is a member of a large family of proteins that regulate the function of heterotrimeric G proteins (Berman and Gilman 1998). RGS9-2 is highly enriched within striatum Gold et al 1997, Rahman et al 1999, where it is implicated in the regulation of dopamine receptor signaling. It was, therefore, of interest to study levels of this protein in the striatum of patients with Parkinsn’s disease.

Section snippets

Isolation of tissue and measures of dopamine function

The brains of 14 patients with Parkinson’s disease, and nine age-matched controls with no neurologic or psychiatric disorder, were obtained from the Royal University Hospital, Saskatoon, Saskatchewan, Canada. Two additional controls were added from the Douglas Hospital Research Center brain bank, Montreal, Canada. Permission for autopsy and inclusion in research studies was obtained from the next of kin at time of autopsy (Calon F et al, unpublished data, 2001). All Parkinson’s disease patients

ΔFosB and RGS9 expression

Levels of ΔFosB and of RGS9-2, analyzed by western blotting, were significantly increased in the putamen and caudate nucleus in individuals with Parkinson’s disease relative to controls (see Figure 1A). In contrast, levels of several other proteins, namely, the catalytic subunit of protein kinase A (which is also involved in dopamine signaling), as well as the cytoskeletal proteins α-tubulin and neurofilament protein-160, were indistinguishable between Parkinson’s disease and control samples

Discussion

The increase in ΔFosB levels demonstrated here in striatum of Parkinson’s disease patients is consistent with earlier work in rodents and nonhuman primates, where denervation of the dopamine system has been shown to induce ΔFosB within the dorsal striatum (see Introduction). In these animal models, ΔFosB induction can persist for several months, which is also consistent with our observation of elevated ΔFosB levels in patients with a many-year history of the disease. In denervated animals,

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