| dc.contributor |
Benjamin B . Gelman , MD , PhD |
|
| dc.contributor |
Miles W . Cloyd , PhD |
|
| dc.contributor |
David J . McAdoo , PhD |
|
| dc.contributor |
Claudio A . Soto , PhD |
|
| dc.contributor |
Dennis L . Kolson , MD , PhD |
|
| dc.creator |
Nguyen , Trung Phuoc |
|
| dc.date |
2010 -09 -28 |
|
| dc.date.accessioned |
2011 -04 -27T21 :39 :51Z |
|
| dc.date.available |
2011 -04 -27T21 :39 :51Z |
|
| dc.date.issued |
2011 -04 -27T21 :39 :51Z |
|
| dc.identifier |
http : / /etd .utmb .edu /theses /available /etd -02202009 -130702 / |
|
| dc.identifier.uri |
http : / /hdl .handle .net /2249 .1 /35812 |
|
| dc.description |
Human immunodeficiency virus -1 (HIV ) infection of the central nervous system results in a syndrome of neuropsychological impairment , motor deficits , and behavioral changes diagnosed as HIV -associated dementia . Findings of increased ubiquitin -stained deposits and high molecular weight ubiquitin -protein conjugates in brains of HIV -positive subjects suggest impaired protein turnover by the ubiquitin -proteasome system analogous to neurodegenerative disorders such as Alzheimers disease and Parkinsons disease . HIV infection of the brain and the consequent inflammatory response was hypothesized to alter the ubiquitin -proteasome system , leading to altered brain protein turnover and neuronal function . Investigations into the ubiquitin -proteasome system in HIV -infected brains were performed using the resources of the Texas NeuroAIDS Research Center and the National NeuroAIDS Tissue Consortium , including clinical data and frontal cortex brain tissue from 153 autopsy cases . Assessment of frontal cortex proteasome proteolytic activity revealed an abnormal catalytic profile that was more severe in those with HIV -associated neuropsychological impairment or HIV encephalitis . Proteasome subunit composition analysis by immunoblotting showed increases in immunoproteasome subunits LMP7 and PA28 alpha and decreases in constitutive proteasome regulatory subunit Rpn2 in the frontal cortex of HIV -positive subjects that correlated with the abnormal proteasome proteinase profile and were associated with neuropsychological impairment and HIV encephalitis . Immunoproteasome increases correlated with lower performance on neurocognitive tests specific for frontal lobe functioning domains , providing indications of regional specificity . Immunoproteasome increases also correlated with increases in frontal cortex tissue HIV loads . Immunoproteasomes were localized by immunofluorescence to the perikarya and distal processes of neurons , as well as to oligodendrocytes , astrocytes , and microglia . The potential consequence of immunoproteasomes in neurons was investigated with the analysis of synaptic proteins . Decreases in synaptophysin correlated with immunoproteasome increases , indicating the potential for synaptic protein alterations associated with immunoproteasomes . Analysis of isolated nerve endings , or synaptosomes , revealed immunoproteasome increases in synapses of HIV -positive subjects that correlated with increases in 14 -3 -3 zeta and decreases in synapsin 1 . These findings suggest hijacking of constitutive proteasomes by immunoproteasomes with the persistent inflammatory response in HIV -infected brains . Ubiquitin -mediated protein turnover by constitutive proteasomes is consequently impaired , resulting in the dysregulation of neuronal and synaptic protein composition that leads to neuronal dysfunction . |
|
| dc.format |
application /pdf |
|
| dc.language |
en |
|
| dc.publisher |
UTMB |
|
| dc.rights |
restricted |
|
| dc.rights |
I hereby certify that , if appropriate , I have obtained and attached hereto a written permission statement from the owner (s ) of each third party copyrighted matter to be included in my thesis , dissertation , or project report , allowing distribution as specified below . I certify that the version I submitted is the same as that approved by my advisory committee . I hereby grant to University of Texas Medical Branch or its agents the non -exclusive license to archive and make accessible , under the conditions specified below , my thesis , dissertation , or project report in whole or in part in all forms of media , now or hereafter known . I retain all other ownership rights to the copyright of the thesis , dissertation or project report . I also retain the right to use in future works (such as articles or books ) all or part of this thesis , dissertation , or project report . |
|
| dc.source |
http : / /etd .utmb .edu /theses /available /etd -02202009 -130702 / |
|
| dc.subject |
Neuroscience & Cell Biology |
|
| dc.title |
Persistent Hijacking of Brain Proteasomes in HIV -Associated Dementia |
|
| dc.type |
text |
|