What would Dr. James Parkinson think today? II. Neuroimaging in Parkinson’s disease

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136297/1/mds26951.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136297/2/mds26951_am.pd

Complementary motivational roles of nigroaccumbens and nigrostriatal dopaminergic pathways

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147822/1/mds27504_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147822/2/mds27504.pd

Many genes involved in Tourette syndrome pathogenesis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137748/1/mds27070.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137748/2/mds27070_am.pd

In vivo evidence for NMDA receptor mediated excitotoxicity in a murine genetic model of Huntington Disease

N-methyl-D-aspartate receptor (NMDAR) mediated excitotoxicity is implicated as a proximate cause of neurodegeneration in Huntington Disease (HD). However, this hypothesis has not been tested rigorously in vivo. NMDAR NR2B-subunits are the predominant NR2 subunit expressed by the striatal medium spiny neurons that degenerate in HD. To test this hypothesis, we crossed a well validated murine genetic model of HD (Hdh(CAG)150) with a transgenic line overexpressing NMDAR NR2B-subunits. In the resulting double mutant line, we show exacerbation of selective striatal neuron degeneration. These results provide the first direct in vivo evidence of NR2B-NMDAR mediated excitotoxicity in the context of HD. Our results are consistent with prior suggestions that direct and/or indirect interactions of mutant huntingtin with NMDARs are a proximate cause of neurodegeneration in HD

Receptor Binding Techniques

This overview first discusses issues relating to the selection of radioligand for receptor binding assays, including the isotopic label and considerations pertaining to the pharmacological and chemical profile of the ligand. This is followed by a section on characterization of ligand‐binding assays, starting with tissue preparation methods, followed by detection of specific binding, determination of incubation and washing conditions and a discussion of saturation and competition assay formats. Quantification of the assay results can be accomplished by autoradiography or film densitometry. Finally, methods and considerations for analysis of the resulting data are presented.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143702/1/cpns0104.pd

A Failed Future

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156468/2/mds28130.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156468/1/mds28130_am.pd

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Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34959/1/1086_ftp.pd

The pleiotropic gene theory of senescence: Supportive evidence from human genetic disease

Senescence is a universal but poorly understood phenomenon among metazoans. One theoretically convincing but unproven evolutionary theory of senescence is the pleitropic gene theory of Williams (1957). This paper develops the hypothesis that some human genetic diseases exemplify the type of phenotypic effects predicted by this theory. The evidence supporting this contention is reviewed and ways of testing this hypothesis are suggested. Other human genetic diseases could be examined in the same manner. Confirmation of this theory would have significant implications for the study of aging.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27085/1/0000076.pd

Microbial controls on net production of nitrous oxide in a denitrifying woodchip bioreactor

Denitrifying woodchip bioreactors are potential low-cost technologies for the removal of nitrate (NO3-) in water through denitrification. However, if environmental conditions do not support microbial communities performing complete denitrification, other N transformation processes will occur, resulting in the export of nitrite (NO2-), nitrous oxide (N2O), or ammonium (NH4+). To identify the factors controlling the relative accumulation of NO2-, N2O, and/or NH4+ in denitrifying woodchip bioreactors, porewater samples were collected over two operational years from a denitrifying woodchip bioreactor designed for removing NO3- from mine water. Woodchip samples were collected at the end of the operational period. Changes in the abundances of functional genes involved in denitrification, N2O reduction, and dissimilatory NO3- reduction to NH4+ were correlated with porewater chemistry and temperature. Temporal changes in the abundance of the denitrification gene nirS were significantly correlated with increases in porewater N2O concentrations and indicated the preferential selection of incomplete denitrifying pathways ending with N2O. Temperature and the total organic carbon/NO3- ratio were strongly correlated with NH4+ concentrations and inversely correlated with the ratio between denitrification genes and the genes indicative of ammonification (sigma nir/nrfA), suggesting an environmental control on NO3- transformations. Overall, our results for a denitrifying woodchip bioreactor operated at hydraulic residence times of 1.0-2.6 d demonstrate the temporal development in the microbial community and indicate an increased potential for N2O emissions with time from the denitrifying woodchip bioreactor

Astrocytic Redox Remodeling by Amyloid Beta Peptide

Abstract Astrocytes are critical for neuronal redox homeostasis providing them with cysteine needed for glutathione synthesis. In this study, we demonstrate that the astrocytic redox response signature provoked by amyloid beta (A-) is distinct from that of a general oxidant (tertiary-butylhydroperoxide [t-BuOOH]). Acute A- treatment increased cystathionine --synthase (CBS) levels and enhanced transsulfuration flux in contrast to repeated A- exposure, which decreased CBS and catalase protein levels. Although t-BuOOH also increased transsulfuration flux, CBS levels were unaffected. The net effect of A- treatment was an oxidative shift in the intracellular glutathione/glutathione disulfide redox potential in contrast to a reductive shift in response to peroxide. In the extracellular compartment, A-, but not t-BuOOH, enhanced cystine uptake and cysteine accumulation, and resulted in remodeling of the extracellular cysteine/cystine redox potential in the reductive direction. The redox changes elicited by A- but not peroxide were associated with enhanced DNA synthesis. CBS activity and protein levels tended to be lower in cerebellum from patients with Alzheimer's disease than in age-matched controls. Our study suggests that the alterations in astrocytic redox status could compromise the neuroprotective potential of astrocytes and may be a potential new target for therapeutic intervention in Alzheimer's disease. Antioxid. Redox Signal. 14, 2385-2397.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90483/1/ars-2E2010-2E3681.pd