Neurochemical investigations of dopamine neuronal systems in iron-regulatory protein 2 (IRP-2) knockout mice

Salvatore, Michael F.; Fisher, Brent; Surgener, Stewart P.; Gerhardt, Greg A.; Rouault, Tracey A.

doi:10.1016/j.molbrainres.2005.06.002

Cited by 35 publications

(34 citation statements)

References 29 publications

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“…The remaining buffer was archived and the protein pellet was sonicated in 1% SDS with 5 mM Tris buffer (pH 8.3) and 1 mM EDTA for determination of total protein, TH protein, and site-specific TH phosphorylation. This methodology matches L-DOPA and DA tissue content with the total recovered TH protein and TH phosphorylation in each sample, as previously reported [14], [27] and since replicated in other laboratories [28].…”

Section: Methodssupporting

confidence: 67%

Dichotomy of Tyrosine Hydroxylase and Dopamine Regulation between Somatodendritic and Terminal Field Areas of Nigrostriatal and Mesoaccumbens Pathways

2012

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Measures of dopamine-regulating proteins in somatodendritic regions are often used only as static indicators of neuron viability, overlooking the possible impact of somatodendritic dopamine (DA) signaling on behavior and the potential autonomy of DA regulation between somatodendritic and terminal field compartments. DA reuptake capacity is less in somatodendritic regions, possibly placing a greater burden on de novo DA biosynthesis within this compartment to maintain DA signaling. Therefore, regulation of tyrosine hydroxylase (TH) activity may be particularly critical for somatodendritic DA signaling. Phosphorylation of TH at ser31 or ser40 can increase activity, but their impact on L-DOPA biosynthesis in vivo is unknown. Thus, determining their relationship with L-DOPA tissue content could reveal a mechanism by which DA signaling is normally maintained. In Brown-Norway Fischer 344 F1 hybrid rats, we quantified TH phosphorylation versus L-DOPA accumulation. After inhibition of aromatic acid decarboxylase, L-DOPA tissue content per recovered TH protein was greatest in NAc, matched by differences in ser31, but not ser40, phosphorylation. The L-DOPA per catecholamine and DA turnover ratios were significantly greater in SN and VTA, suggesting greater reliance on de novo DA biosynthesis therein. These compartmental differences reflected an overall autonomy of DA regulation, as seen by decreased DA content in SN and VTA, but not in striatum or NAc, following short-term DA biosynthesis inhibition from local infusion of the TH inhibitor α-methyl-p-tyrosine, as well as in the long-term process of aging. Such data suggest ser31 phosphorylation plays a significant role in regulating TH activity in vivo, particularly in somatodendritic regions, which may have a greater reliance on de novo DA biosynthesis. Thus, to the extent that somatodendritic DA release affects behavior, TH regulation in the midbrain may be critical for DA bioavailability to influence behavior.

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Section: Methodssupporting

confidence: 67%

Dichotomy of Tyrosine Hydroxylase and Dopamine Regulation between Somatodendritic and Terminal Field Areas of Nigrostriatal and Mesoaccumbens Pathways

2012

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“…For example, Fe 2ϩ regulation has been proposed to affect expression levels of DAT or tyrosine hydroxylase, the rate-limiting enzyme for dopamine (81). DAT transports 6-OHDA into DA neurons and has been proposed to play a role in DA neuron vulnerability to environmental toxicants (49,82,83).…”

Section: Discussionmentioning

confidence: 99%

“…A reduction in DAT in the SMF mutant animals could result in lower quantities of toxicants entering the cell with a concomitant decrease in cell death. Tyrosine hydroxylase also requires Fe 2ϩ as a cofactor, and a reduction in Fe 2ϩ has been shown to decrease tyrosine hydroxylase and dopaminergic activity, which could result in decreases in susceptibility to DA neuronal insult (81,84). Furthermore, DAT is also a target for Mn 2ϩ , and exposure to Mn 2ϩ has been shown to increase DAT surface expression that could result in increases in neuronal vulnerability (85).…”

Section: Discussionmentioning

confidence: 99%

The Divalent Metal Transporter Homologues SMF-1/2 Mediate Dopamine Neuron Sensitivity in Caenorhabditis elegans Models of Manganism and Parkinson Disease

Settivari

LeVora

Nass

2009

Journal of Biological Chemistry

119

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Parkinson disease (PD) and manganism are characterized by motor deficits and a loss of dopamine (DA) neurons in the substantia nigra pars compacta. Epidemiological studies indicate significant correlations between manganese exposure and the propensity to develop PD. The vertebrate divalent metal transporter-1 (DMT-1) contributes to maintaining cellular Mn 2؉ homeostasis and has recently been implicated in Fe 2؉ -mediated neurodegeneration in PD. In this study we describe a novel model for manganism that incorporates the genetically tractable nematode Caenorhabditis elegans. We show that a brief exposure to Mn 2؉ increases reactive oxygen species and glutathione production, decreases oxygen consumption and head mitochondria membrane potential, and confers DA neuronal death. DA neurodegeneration is partially dependent on a putative homologue to DMT-1, SMF-1, as genetic knockdown or deletion partially inhibits the neuronal death. Mn 2؉ also amplifies the DA neurotoxicity of the PD-associated protein ␣-synuclein. Furthermore, both SMF-1 and SMF-2 are expressed in DA neurons and contribute to PD-associated neurotoxicant-induced DA neuron death. These studies describe a C. elegans model for manganism and show that DMT-1 homologues contribute to Mn 2؉ -and PD-associated DA neuron vulnerability.Manganese is the second most prevalent transition metal and is an essential trace element that is necessary for normal growth and development. The heavy metal is required for a number of biological processes, including amino acid, lipid, and carbohydrate production, and metabolism, and is a cofactor for a diverse set of proteins, including arginases, transferases, hydrolases, ligases, and oxidoreductases (1, 2). Deficiencies in Mn 2ϩ , although rare, have been linked with bone malformation, hypertension, osteoporosis, and epilepsy (3, 4). Mn 2ϩ is also a potent neurotoxicant, and occupational exposure to high concentrations of the metal can result in a neurological condition called manganism (1, 5). Symptoms of manganism include tremors, bradykinesia, rigidity, and facial muscle spasms (1, 6, 7). Mn 2ϩ neurotoxicity has been associated with a number of occupational and environmental exposures. High incidence of manganism has been found in manganese miners and smelters (7-10). Welders appear to be particularly vulnerable to the disorder as manganese alloys used in the heating and joining of metals may result in the production and inhalation of manganese particles (11). Exposure to Mn 2ϩ -based pesticides, including maneb and mancozeb, has also been associated with the development of manganism (12)(13)(14). Furthermore, significant environmental exposures have been reported with water contamination and possibly with the manganese-containing anti-knock fuel additive methylcyclopentadienyl manganese tricarbonyl (12). Recently, high exposures to Mn 2ϩ have also been associated with psychoactive stimulant preparations for recreational drug use (15,16).Epidemiological studies suggest a significant correlation of exposure to high concent...

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“…To characterize the dopamine (DA) system in these Irp2 −/− mice, Salvatore et al harvested CNS tissue from 16–19 month-old WT and Irp2 −/− animals, and observed a modest decrease of tyrosine hydroxylase (TH) and an increase in phosphorylation of serine 40 of TH in both the dorsal and ventral striata of Irp2 −/− mice in comparison to those of WT controls (Salvatore et al, 2005). These researchers also found a moderate decrease in dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) levels and a mild decrease in DA levels in the ventral striatum, but not in the dorsal striatum of Irp2 −/− mice, supporting that misregulation of iron in Irp2 −/− animals affects DA regulation in the striatum.…”

Section: The First Irp2 Knockout Mouse Modelmentioning

confidence: 99%

Iron misregulation and neurodegenerative disease in mouse models that lack iron regulatory proteins

Ghosh¹,

Zhang²,

Rouault³

2015

Neurobiology of Disease

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Iron regulatory proteins 1 and 2 (IRP1 and IRP2) are two cytosolic proteins that maintain cellular iron homeostasis by binding to RNA stem loops known as iron responsive elements (IREs) that are found in the untranslated regions of target mRNAs that encode proteins involved in iron metabolism. IRPs modify expression of iron metabolism genes, and global and tissue-specific knockout mice have been made to evaluate the physiological significance of these iron regulatory proteins (Irps). Here, we will discuss the results of the studies that have been performed with mice engineered to lack expression of one or both Irps, and made in different strains using different methodologies. Both Irp1 and Irp2 knockout mice are viable, but the double knockout (Irp1−/−Irp2−/−) mice die before birth, indicating that these Irps play a crucial role in maintaining iron homeostasis. Irp1−/− mice develop polycythemia and pulmonary hypertension, and when these mice are challenged with a low iron diet, they die early of abdominal hemorrhages, suggesting that Irp1 plays an essential role in erythropoiesis and in the pulmonary and cardiovascular systems. Irp2−/− mice develop microcytic anemia, erythropoietic protoporphyria and a progressive neurological disorder, indicating that Irp2 has important functions in the nervous system and erythropoietic homeostasis. Several excellent review articles have recently been published on Irp knockout mice that mainly focus on Irp1−/− mice (referenced in the introduction). In this review, we will briefly describe the phenotypes and physiological implications of Irp1−/− mice, and will discuss the phenotypes observed for Irp2−/− mice in detail with a particular emphasis on the neurological problems of these mice.

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Neurochemical investigations of dopamine neuronal systems in iron-regulatory protein 2 (IRP-2) knockout mice

Cited by 35 publications

References 29 publications

Dichotomy of Tyrosine Hydroxylase and Dopamine Regulation between Somatodendritic and Terminal Field Areas of Nigrostriatal and Mesoaccumbens Pathways

Dichotomy of Tyrosine Hydroxylase and Dopamine Regulation between Somatodendritic and Terminal Field Areas of Nigrostriatal and Mesoaccumbens Pathways

The Divalent Metal Transporter Homologues SMF-1/2 Mediate Dopamine Neuron Sensitivity in Caenorhabditis elegans Models of Manganism and Parkinson Disease

Iron misregulation and neurodegenerative disease in mouse models that lack iron regulatory proteins

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