東華大學圖書館 |

語系: 繁體中文

說明(常見問題)

回圖書館首頁

手機版館藏查詢

登入

回首頁

切換: 標籤 | MARC模式 | ISBD

An evaluation of the molecular model...

Fredenburg, Ross Allen.

FindBook

Google Book

Amazon

博客來

An evaluation of the molecular model of alpha-synuclein-mediated cytotoxicity.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	An evaluation of the molecular model of alpha-synuclein-mediated cytotoxicity./
作者:	Fredenburg, Ross Allen.
面頁冊數:	168 p.
附註:	Source: Dissertation Abstracts International, Volume: 67-02, Section: B, page: 0867.
Contained By:	Dissertation Abstracts International67-02B.
標題:	Biology, Cell. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3205899
ISBN:	9780542544491

An evaluation of the molecular model of alpha-synuclein-mediated cytotoxicity.
Fredenburg, Ross Allen.

An evaluation of the molecular model of alpha-synuclein-mediated cytotoxicity. - 168 p.

Source: Dissertation Abstracts International, Volume: 67-02, Section: B, page: 0867.

Thesis (Ph.D.)--Harvard University, 2006.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of a specific subset of neurons in the midbrain and the intracellular deposition of amyloid fibrils composed of the presynaptic protein alpha-synuclein. Three point mutants of alpha-synuclein have been linked to rare cases of familial PD, thus confirming that alpha-synuclein plays an integral role in the pathogenic process that leads to neurodegeneration. Considerable evidence indicates that aggregation of alpha-synuclein leads to a toxic gain of function, but the precise molecular mechanisms by which alpha-synuclein mediates this toxicity within cells have not been determined. One proposed model of alpha-synuclein-induced cytotoxicity involves the transient formation of soluble oligomeric species that are possible intermediates in the process of amyloid fibril formation. These protofibrils possess membrane-permeabilizing activity, and their action could account for the alpha-synuclein-dependent toxicity observed in the absence of detectable fibril formation in certain cell culture models. The recent discovery of novel variants of alpha-synuclein that may play a role in the development of both familial and sporadic PD provides an opportunity to evaluate the predictive ability of the model in terms of alpha-synuclein cellular toxicity. E46K alpha-synuclein was identified as the most recent genetic link between alpha-synuclein and PD. S129E alpha-synuclein serves as a stable mimic of serine phosphorylation of alpha-synuclein, a modification that has been associated with amyloid deposits in human brain. The D98A/Q99A double mutant was constructed to interfere with the lysosomal degradation of alpha-synuclein, in order to better understand the role of the lysosome in the regulation of alpha-synuclein toxicity. Each variant was characterized in terms of fibrillization rate, protofibril formation, membrane permeabilization activity, and yeast cell toxicity. The general correlation between the in vitro predictors of toxicity and an initial toxicity assessment in yeast supports the hypothesis that a soluble aggregate species mediates alpha-synuclein toxicity. Certain inconsistencies with the protofibril-based toxicity model suggest refinements that could improve the utility of the model in directing further research in the field.

ISBN: 9780542544491Subjects--Topical Terms:

1017686
Biology, Cell.

An evaluation of the molecular model of alpha-synuclein-mediated cytotoxicity.
LDR:03265nmm 2200289 4500 001 1834296
005 20071119145613.5
008 130610s2006 eng d
020 $a 9780542544491
035 $a (UMI)AAI3205899
035 $a AAI3205899
040 $a UMI $c UMI
100 1 $a Fredenburg, Ross Allen. $3 1922957
245 1 3 $a An evaluation of the molecular model of alpha-synuclein-mediated cytotoxicity.
300 $a 168 p.
500 $a Source: Dissertation Abstracts International, Volume: 67-02, Section: B, page: 0867.
500 $a Adviser: Peter T. Lansbury, Jr.
502 $a Thesis (Ph.D.)--Harvard University, 2006.
520 $a Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of a specific subset of neurons in the midbrain and the intracellular deposition of amyloid fibrils composed of the presynaptic protein alpha-synuclein. Three point mutants of alpha-synuclein have been linked to rare cases of familial PD, thus confirming that alpha-synuclein plays an integral role in the pathogenic process that leads to neurodegeneration. Considerable evidence indicates that aggregation of alpha-synuclein leads to a toxic gain of function, but the precise molecular mechanisms by which alpha-synuclein mediates this toxicity within cells have not been determined. One proposed model of alpha-synuclein-induced cytotoxicity involves the transient formation of soluble oligomeric species that are possible intermediates in the process of amyloid fibril formation. These protofibrils possess membrane-permeabilizing activity, and their action could account for the alpha-synuclein-dependent toxicity observed in the absence of detectable fibril formation in certain cell culture models. The recent discovery of novel variants of alpha-synuclein that may play a role in the development of both familial and sporadic PD provides an opportunity to evaluate the predictive ability of the model in terms of alpha-synuclein cellular toxicity. E46K alpha-synuclein was identified as the most recent genetic link between alpha-synuclein and PD. S129E alpha-synuclein serves as a stable mimic of serine phosphorylation of alpha-synuclein, a modification that has been associated with amyloid deposits in human brain. The D98A/Q99A double mutant was constructed to interfere with the lysosomal degradation of alpha-synuclein, in order to better understand the role of the lysosome in the regulation of alpha-synuclein toxicity. Each variant was characterized in terms of fibrillization rate, protofibril formation, membrane permeabilization activity, and yeast cell toxicity. The general correlation between the in vitro predictors of toxicity and an initial toxicity assessment in yeast supports the hypothesis that a soluble aggregate species mediates alpha-synuclein toxicity. Certain inconsistencies with the protofibril-based toxicity model suggest refinements that could improve the utility of the model in directing further research in the field.
590 $a School code: 0084.
650 4 $a Biology, Cell. $3 1017686
650 4 $a Chemistry, Biochemistry. $3 1017722
650 4 $a Health Sciences, Pathology. $3 1017854
690 $a 0379
690 $a 0487
690 $a 0571
710 2 0 $a Harvard University. $3 528741
773 0 $t Dissertation Abstracts International $g 67-02B.
790 1 0 $a Lansbury, Peter T., Jr., $e advisor
790 $a 0084
791 $a Ph.D.
792 $a 2006
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3205899