Elevated levels of ΔFosB and RGS9 in striatum in Parkinson’s disease
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for autopsy and inclusion in research studies was obtained from the next of kin at time of autopsy (Calon F et al, unpublished data, 2001).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,
References (19)
- et al.
Striatal fosB expression is causally linked with L-DOPA-induced abnormal involuntary movements and the associated upregulation of striatal prodynorphin mRNA in a rat model of Parkinson’s disease
Neurobiol Dis
(1999) - et al.
Mammalian RGS proteinsBarbarians at the gate
J Biol Chem
(1998) - et al.
Dopamine-receptor stimulationBiobehavioral and biochemical consequences
Trends Neurosci
(2000) - et al.
Changes in the regional and compartmental distribution of fosB and Jun-like immunoreactivity induced in the dopamine-denervated rat striatum by acute or chronic L-DOPA treatment
Neuroscience
(1999) - et al.
D1-receptor-related priming is attenuated by antisense-mediated ‘knockdown’ of fosB expression
Mol Brain Res
(1998) - et al.
Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments
Neuron
(1994) - et al.
MPTP-Parkinsonism is accompanied by persistent expression of a ΔFosB-like protein in dopaminergic pathways
Mol Brain Res
(1998) - et al.
Region-specific induction of ΔFosB by repeated administration of typical versus atypical antipsychotic drugs
Synapse
(1999) - et al.
Long-term effects of MPTP on central and peripheral catecholamine and indoleamine concentrations in monkeys
Brain Res
(1986)