Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease

Nordstrom, U.,Beauvais, G.,Ghosh, A.,Pulikkaparambil Sasidharan, B.C.,Lundblad, M.,Fuchs, J.,Joshi, R.L.,Lipton, J.W.,Roholt, A.,Medicetty, S.,Feinstein, T.N.,Steiner, J.A.,Escobar Galvis, M.L.,Prochi Blackwell Science ; Academic Press 2015 Neurobiology of disease Vol.73 No.-

Current research on Parkinson's disease (PD) pathogenesis requires relevant animal models that mimic the gradual and progressive development of neuronal dysfunction and degeneration that characterizes the disease. Polymorphisms in engrailed 1 (En1), a homeobox transcription factor that is crucial for both the development and survival of mesencephalic dopaminergic neurons, are associated with sporadic PD. This suggests that En1 mutant mice might be a promising candidate PD model. Indeed, a mouse that lacks one En1 allele exhibits decreased mitochondrial complex I activity and progressive midbrain dopamine neuron degeneration in adulthood, both features associated with PD. We aimed to further characterize the disease-like phenotype of these En1<SUP>+/-</SUP> mice with a focus on early neurodegenerative changes that can be utilized to score efficacy of future disease modifying studies. We observed early terminal defects in the dopaminergic nigrostriatal pathway in En1<SUP>+/-</SUP> mice. Several weeks before a significant loss of dopaminergic neurons in the substantia nigra could be detected, we found that striatal terminals expressing high levels of dopaminergic neuron markers TH, VMAT2, and DAT were dystrophic and swollen. Using transmission electron microscopy, we identified electron dense bodies consistent with abnormal autophagic vacuoles in these terminal swellings. In line with these findings, we detected an up-regulation of the mTOR pathway, concurrent with a downregulation of the autophagic marker LC3B, in ventral midbrain and nigral dopaminergic neurons of the En1<SUP>+/-</SUP> mice. This supports the notion that autophagic protein degradation is reduced in the absence of one En1 allele. We imaged the nigrostriatal pathway using the CLARITY technique and observed many fragmented axons in the medial forebrain bundle of the En1<SUP>+/-</SUP> mice, consistent with axonal maintenance failure. Using in vivo electrochemistry, we found that nigrostriatal terminals in the dorsal striatum were severely deficient in dopamine release and reuptake. Our findings support a progressive retrograde degeneration of En1<SUP>+/-</SUP> nigrostriatal neurons, akin to what is suggested to occur in PD. We suggest that using the En1<SUP>+/-</SUP> mice as a model will provide further key insights into PD pathogenesis, and propose that axon terminal integrity and function can be utilized to estimate dopaminergic neuron health and efficacy of experimental PD therapies.

What was the groundwater quality before mining in a mineralized region? Lessons from the Questa Project

D. Kirk Nordstrom 한국지질과학협의회 2008 Geosciences Journal Vol.12 No.2

The U.S. Geological Survey, in cooperation with the New Mexico Environment Department and supported by Molycorp, Inc (currently Chevron Minerals), has completed a 5-year investigation (2001-2006) to determine the pre-mining groundwater quality at Molycorp’s Questa molybdenum mine in northern New Mexico. Current mine-site ground waters are often contaminated with mine-waste leachates and no data exists on premining ground-water quality so that pre-mining conditions must be inferred. Ground-water quality undisturbed by mining is often worse than New Mexico standards and data are needed to help establish closure requirements. The key to determining pre-mining conditions was to study the hydrogeochemistry of a proximal natural analog site, the Straight Creek catchment. Main rock types exposed to weathering include a Tertiary andesite and the Tertiary Amalia tuff (rhyolitic composition), both hydrothermally altered to various degrees. Two types of ground water are common in mineralized areas, acidic ground waters in alluvial debris fans with pH 3-4 and bedrock ground waters with pH 6-8. Siderite, ferrihydrite, rhodochrosite, amorphous to microcrystalline Al(OH)3, calcite, gypsum, barite, and amorphous silica mineral solubilities control concentrations of Fe(II), Fe(III), Mn(II), Al, Ca, Ba, and SiO2, depending on pH and solution composition. Concentrations at low pH are governed by element abundance and mineral weathering rates. Concentrations of Zn and Cd range from detection up to about 10 and 0.05 mg/L, respectively, and are derived primarily from sphalerite dissolution. Concentrations of Ni and Co range from detection up to 1 and 0.4 mg/L, respectively, and are derived primarily from pyrite dissolution. Concentrations of Ca and SO4 are derived from secondary gypsum dissolution and weathering of calcite and pyrite. Metal:sulfate concentration ratios are relatively constant for acidic waters, suggesting consistent weathering rates, independent of catchment. These trends, combined with lithology, mineralogy, and mineral solubility controls, provide useful constraints on pre-mining ground-water quality for the mine site where the lithology is known The U.S. Geological Survey, in cooperation with the New Mexico Environment Department and supported by Molycorp, Inc (currently Chevron Minerals), has completed a 5-year investigation (2001-2006) to determine the pre-mining groundwater quality at Molycorp’s Questa molybdenum mine in northern New Mexico. Current mine-site ground waters are often contaminated with mine-waste leachates and no data exists on premining ground-water quality so that pre-mining conditions must be inferred. Ground-water quality undisturbed by mining is often worse than New Mexico standards and data are needed to help establish closure requirements. The key to determining pre-mining conditions was to study the hydrogeochemistry of a proximal natural analog site, the Straight Creek catchment. Main rock types exposed to weathering include a Tertiary andesite and the Tertiary Amalia tuff (rhyolitic composition), both hydrothermally altered to various degrees. Two types of ground water are common in mineralized areas, acidic ground waters in alluvial debris fans with pH 3-4 and bedrock ground waters with pH 6-8. Siderite, ferrihydrite, rhodochrosite, amorphous to microcrystalline Al(OH)3, calcite, gypsum, barite, and amorphous silica mineral solubilities control concentrations of Fe(II), Fe(III), Mn(II), Al, Ca, Ba, and SiO2, depending on pH and solution composition. Concentrations at low pH are governed by element abundance and mineral weathering rates. Concentrations of Zn and Cd range from detection up to about 10 and 0.05 mg/L, respectively, and are derived primarily from sphalerite dissolution. Concentrations of Ni and Co range from detection up to 1 and 0.4 mg/L, respectively, and are derived primarily from pyrite dissolution. Concentrations of Ca and SO4 are derived from secondary gypsum dissolution and weathering of calcite and pyrite. Metal:sulfate concentration ratios are relatively constant for acidic waters, suggesting consistent weathering rates, independent of catchment. These trends, combined with lithology, mineralogy, and mineral solubility controls, provide useful constraints on pre-mining ground-water quality for the mine site where the lithology is known

BINARY STARS AND CLUSTERS AS TESTS OF STELLAR EVOLUTION MODELS

ANDERSEN J.,NORDSTROM B. The Korean Astronomical Society 1996 Journal of The Korean Astronomical Society Vol.29 No.suppl1

Precise masses, radii, and luminosities from eclipsing binaries and colour-magnitude diagrams for open clusters are classic tools in empirical tests of stellar evolution models. We review the accuracy and completeness required for such data to discriminate between current models and describe some recent. results with implications for convection theory.

EVOLUTION OF THE GALACTIC DISK: FOCUS ON THE SOLAR NEIGHBOURHOOD

ANDERSEN J.,NORDSTROM B.,OLSEN E. H.,MAYOR M.,PONT F. The Korean Astronomical Society 1996 Journal of The Korean Astronomical Society Vol.29 No.suppl1

The solar neighbourhood is the starting point for studies of the structure and evolution of the Galactic disk. Yet, our knowledge of the relative frequencies, distances, ages, chemical abundances, velocities, and birthplaces of the nearby stars is severely incomplete. We have determined complete, homogeneous, and precise such data for a kinematically unbiased sample of $\~$12,000 local F and G dwarf stars and describe a first, significant result from it.