Regional Metal Concentrations in Parkinson's Disease, Other Chronic Neurological Diseases, and Control Brains

Uitti, Ryan J.; Rajput, Ali H.; Rozdilsky, B.; Bickis, Mikelis G.; Wollin, T.; Yuen, WH

doi:10.1017/s0317167100029140

Cited by 121 publications

(76 citation statements)

References 22 publications

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“…On the other hand, magnesium levels are reduced in brains of patients with PD (21)(22)(23)(24)(25)(26). If iron accelerates ␣-synuclein aggregation, then the abundance of iron in the substantia nigra could increase the tendency of Lewy bodies to accumulate in this region.…”

Section: Discussionmentioning

confidence: 99%

Magnesium Inhibits Spontaneous and Iron-induced Aggregation of α-Synuclein

Golts

Snyder

Frasier

et al. 2002

Journal of Biological Chemistry

191

144

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Multiple studies implicate metals in the pathophysiology of neurodegenerative diseases. Disturbances in brain iron metabolism are linked with synucleinopathies. For example, in Parkinson's disease, iron levels are increased and magnesium levels are reduced in the brains of patients. To understand how changes in iron and magnesium might affect the pathophysiology of Parkinson's disease, we investigated binding of iron to ␣-synuclein, which accumulates in Lewy bodies. Using fluorescence of the four tyrosines in ␣-synuclein as indicators of metal-related conformational changes in ␣-synuclein, we show that iron and magnesium both interact with ␣-synuclein. ␣-Synuclein exhibits fluorescence peaks at 310 and 375 nm. Iron lowers both fluorescence peaks, while magnesium increases the fluorescence peak only at 375 nm, which suggests that magnesium affects the conformation of ␣-synuclein differently than iron. Consistent with this hypothesis, we also observe that magnesium inhibits ␣-synuclein aggregation, measured by immunoblot, cellulose acetate filtration, or thioflavine-T fluorescence. In each of these studies, iron increases ␣-synuclein aggregation, while magnesium at concentrations >0.75 mM inhibits the aggregation of ␣-synuclein induced either spontaneously or by incubation with iron. These data suggest that the conformation of ␣-synuclein can be modulated by metals, with iron promoting aggregation and magnesium inhibiting aggregation. Parkinson's disease (PD)1 is a common motor disorder that affects about 1% of population over the age of 65 (1). The disease is characterized by progressive neurodegeneration predominantly affecting dopaminergic neurons in the nigrostriatal system (2). The degenerating neurons develop intracellular inclusions, termed Lewy bodies, which are composed of a dense core of filamentous and granular material (3). Recent studies indicate that ␣-synuclein is a major filamentous component of Lewy bodies (3,4). Genetic studies suggest that ␣-synuclein plays a key role in the pathophysiology of PD, because mutations in ␣-synuclein, at A53T or A30P, are associated with early-onset familial PD (5, 6).The accumulation of aggregated protein underlies the pathophysiology of many neurodegenerative disorders, and increasing evidence suggests that aggregated ␣-synuclein plays a key role in the pathophysiology of PD. ␣-Synuclein has a strong tendency to aggregate and does so spontaneously in vitro at a slow rate (7-9). Both the A53T and the A30P mutations in PD increase the tendency of ␣-synuclein to aggregate. Many studies in cultured neurons, and some studies in transgenic animals, suggest that ␣-synuclein aggregation is linked to cellular toxicity and neurodegeneration (10 -12). In cell culture, formation of ␣-synuclein aggregates correlates with cell injury (10). Overexpressing ␣-synuclein in Drosophila leads to an age-dependent accumulation of aggregated ␣-synuclein and associated neurodegeneration (12). Masliah and colleagues also observed that aggregated ␣-synuclein is associated with loss of marke...

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Section: Discussionmentioning

confidence: 99%

Magnesium Inhibits Spontaneous and Iron-induced Aggregation of α-Synuclein

Golts

Snyder

Frasier

et al. 2002

Journal of Biological Chemistry

191

144

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“…at 90th minute following the MPTP or saline injection and were decapitated at 120th minute. Brains were quickly removed for used immediately or stored at -70~ Methods -Determination of total iron concentration in striata: total iron concentration in striata were determined by atomic absorption and emission spectroscopy, using a method similar to that reported by Uitti et al (1989). -Determination of GSSG and total glutathione (GSSG + GSH): following decapitation, frontal cortices were rapidly excised over ice and the tissues homogenized in 10 volumes of 0.4 mol/L cold perchloric acid (PCA) containing 0.1 mmol/L diethylenetriamine-pentaacetic acid and centrifugated at 10,000 g for 5 minutes at 4~ Supernatants were analyzed immediately for GSH and GSSG concentrations by an enzymatic recycling procedure, as described by Tietze (1969) and modified by Cooper et al (1980), based on the activity of glutathione reductase.…”

Section: Animals and Treatmentsmentioning

confidence: 99%

Desferrioxamine and vitamin E protect against iron and MPTP-induced neurodegeneration in mice

Lan

Jiang

1997

J. Neural Transmission

151

112

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Summary.To elucidate the neuroprotective effects of the iron chelator desferrioxamine (DFO) and the antioxidant vitamin E on excessive ironinduced free radical damage, a chronic iron-loaded mice model was established. The relationship between striatal iron content, oxidized to reduced glutathione ratio, hydroxyl radical ('OH) levels and dopamine concentrations were observed in DFO or vitamin E pretreated iron-loaded/1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP)-treated C57BL/6 mice. The results demonstrated that both DFO and vitamin E inhibit the iron accumulation and thus reverses the increase in oxidized glutathione (GSSG), oxidized to reduced glutathione ratios, "OH and lipid peroxidation levels. The striatal dopamine concentration was elevated to normal value. Our data suggested that: (1) iron may induce neuronal damage and thus excessive iron in the brain may contribute to the neuronal loss in PD; (2) iron chelators and antioxidants may serve as potential therapeutic agents in retarding the progression of neurodegeneration.

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“…The brains were quickly removed for used immediately or stored at -70~ Methods 1. Determination of total iron concentration in striatum: total iron concentration in striatum was determined by atomic absorption and emission spectroscopy using a method similar to that reported by Uitti et al (1989).…”

Section: Animals and Treatmentsmentioning

confidence: 99%

Excessive iron accumulation in the brain: A possible potential risk of neurodegeneration in Parkinson's disease

Lan

Jiang

1997

J. Neural Transmission

100

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In this study a chronic cerebral iron-loaded model was established by feeding mice with high iron diet. Data indicated that brain iron concentrations were significantly increased in iron-fed mice compared with those of controls. A significant increase in oxidized glutathione (GSSG), decrease in total glutathione (oxidized and reduced glutathione, GSSG + GSH), and therefore increase in the GSSG/(GSSG + GSH) ratios were observed in iron-loaded mice. Hydroxyl radical (.OH) levels in striatum and brainstem were also significantly increased. Excessive iron alone did not change either dopamine (DA) or lipid peroxidation (LPO) concentrations in striatum. However, a single injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg, i.p.) into the iron-loaded mice caused a great enhancement in all these biochemical abnormalities. These findings suggest that iron does induce oxidative stress, but not severely injury neurons per sc. Excessive iron accumulation in the brain, however, is a potential risk for neuronal damage, which may promote by triggering factor(s). This supports the hypothesis that excessive cerebral iron may contribute to the aetiology of Parkinson's disease (PD).

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Regional Metal Concentrations in Parkinson's Disease, Other Chronic Neurological Diseases, and Control Brains

Cited by 121 publications

References 22 publications

Magnesium Inhibits Spontaneous and Iron-induced Aggregation of α-Synuclein

Magnesium Inhibits Spontaneous and Iron-induced Aggregation of α-Synuclein

Desferrioxamine and vitamin E protect against iron and MPTP-induced neurodegeneration in mice

Excessive iron accumulation in the brain: A possible potential risk of neurodegeneration in Parkinson's disease

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