A reduction in dopaminergic innervation of the subventricular zone (SVZ) is responsible for the impaired proliferation of its resident precursor cells in this region in Parkinson's disease (PD). Here, we show that this effect involves EGF, but not FGF2. In particular, we demonstrate that dopamine increases the proliferation of SVZ-derived cells by releasing EGF in a PKC-dependent manner in vitro and that activation of the EGF receptor (EGFR) is required for this effect. We also show that dopamine selectively expands the GFAP ؉ multipotent stem cell population in vitro by promoting their self-renewal. Furthermore, in vivo dopamine depletion leads to a decrease in precursor cell proliferation in the SVZ concomitant with a reduction in local EGF production, which is reversed through the administration of the dopamine precursor levodopa (L-DOPA). Finally, we show that EGFR ؉ cells are depleted in the SVZ of human PD patients compared with age-matched controls. We have therefore demonstrated a unique role for EGF as a mediator of dopamine-induced precursor cell proliferation in the SVZ, which has potential implications for future therapies in PD.T he ability of neural stem and progenitor cells in the adult brain to continually proliferate and generate neuronal precursors is of great significance, because manipulation of this endogenous process may stimulate the replacement of cells lost as a consequence of disease. In the adult mammalian brain, the subventricular zone (SVZ) lining the lateral ventricles is 1 of the 2 primary sites of adult neurogenesis (1, 2), and it is in this niche that the first step in the process of neurogenesis (proliferation) occurs, involving neural stem cells (B cells), that proliferate slowly, giving rise to transitamplifying progenitor cells (C cells) (3). Several locally-acting diffusible molecules, such as EGF, control proliferation in the SVZ (4-7). EGF influences SVZ expansion by binding to the EGF receptor (EGFR) that is present on ''activated B cells'' and rapidly dividing C cells (8).The adult SVZ is innervated by dopaminergic fibers that originate in the substantia nigra (9, 10). These dopaminergic projections extending to the SVZ, predominantly contact the C cells and regulate their proliferative capacity (9). Thus in Parkinson's disease (PD), a dramatic reduction in SVZ precursor cell proliferation occurs as a consequence of dopamine depletion. However, the mechanism by which this occurs is unknown, but given that both dopamine and EGF receptors are coexpressed on the C cell, we sought to investigate the hypothesis that EGF was critical to this process. Using a range of in vitro and in vivo studies, we have now shown that dopamine stimulates the release of EGF from cells in the SVZ, which in turn acts on the EGFR to promote proliferation, and that EGFR expression in the SVZ is significantly depleted in PD patients. ResultsAdult SVZ-derived neural precursor cells (NPCs) displayed clear colocalization for the high-affinity dopamine receptor, the D2-like (D2L) receptor, and the EGFR...
Cognitive deficits occur in up to 30% of patients with early Parkinson's disease, some of which are thought to result from dysfunction within the fronto-striatal dopaminergic network. Recently, it has been shown that a common functional polymorphism (Val(158)Met) in the catechol-O-methyltransferase (COMT) gene is associated with changes in executive performance in tasks that have a fronto-striatal basis. This is thought to relate to changes in cortical dopamine levels as catechol-O-methyltransferase is the main mode of inactivation for dopamine in frontal areas. However to date, no study has investigated dopamine turnover as a function of this genetic polymorphism in Parkinson's disease. We, therefore, set out to investigate in vivo changes in presynaptic dopamine storage in patients with idiopathic Parkinson's disease as a function of the catechol-O-methyltransferase Val(158)Met polymorphism using (18)F-DOPA positron emission tomography. Twenty patients with Parkinson's disease (10 homozygous for Val/Val and 10 for Met/Met catechol-O-methyltransferase polymorphisms) underwent (18)F-DOPA positron emission tomography using a prolonged imaging protocol. The first dynamic scan was acquired from 0 to 90 min (early), and the second scan (late) from 150 to 210 min post-intravenous radioligand administration. Patients were matched for age, sex, verbal IQ, disease duration and severity of motor features. (18)F-DOPA influx constants (Ki) were calculated and compared for frontal and striatal regions. Late scan mean frontal and striatal Ki values were significantly reduced in both Parkinson's disease groups relative to early scan Ki values. Met/Met patients had significantly higher late scan Ki values compared with their Val/Val counterparts in anterior cingulate, superior frontal and mid-frontal regions but early frontal Ki values were not different between the two groups. As late Ki values reflect rates of dopamine metabolism to 3,4-dihydroxyphenylacetic acid and homovanillic acid, our results indicate that Met homozygotes have higher presynaptic dopamine levels in frontal regions than Val homozygotes, which may help to explain how this genotypic variation may influence the fronto-striatal cognitive deficits of Parkinson's disease.
Parkinson's (PD) and Huntington's disease (HD) are chronic neurodegenerative conditions of the brain with a variety of clinical presentations including a disorder of movement and a range of nonmotor deficits. HD is genetic in origin and the causative gene and protein known, namely mutant Huntingtin, which leads to widespread early neuronal dysfunction and death throughout the brain. In contrast, the etiology of sporadic PD is unknown, and the pathology targets the nigrostriatal dopaminergic neurons with the formation of alpha-synuclein positive Lewy bodies. In both diseases, the ability to accurately diagnose the disease in the early stages and monitor progression over time remains a major challenge given the majority of the pathology is sited deep within the CNS. This challenge has gained extra significance as the development of disease-modifying drugs starts to emerge into the clinic. To this end, there is a need to find biomarkers that will help in the accurate diagnosis of the disease and/or prediction of its clinical onset as well as biomarkers that are able to faithfully track disease progression independent of any symptomatic effects of any therapies. In addition, these same markers may also help stratify each of these heterogeneous disorders into specific subtypes that share particular clinical and pathological characteristics.
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