國立虎尾科技大學 |

Investigating the role of ubiquitin in endosomal sorting and processing of amyloid precursor protein.

紀錄類型:	書目-語言資料,手稿 : Monograph/item
正題名/作者:	Investigating the role of ubiquitin in endosomal sorting and processing of amyloid precursor protein./
作者:	Williamson, Rebecca.
面頁冊數:	1 online resource (151 pages)
附註:	Source: Dissertation Abstracts International, Volume: 78-06(E), Section: B.
Contained By:	Dissertation Abstracts International78-06B(E).
標題:	Neurosciences. -
電子資源:	click for full text (PQDT)
ISBN:	9781369535532

Investigating the role of ubiquitin in endosomal sorting and processing of amyloid precursor protein.
Williamson, Rebecca.

Investigating the role of ubiquitin in endosomal sorting and processing of amyloid precursor protein. - 1 online resource (151 pages)

Source: Dissertation Abstracts International, Volume: 78-06(E), Section: B.

Thesis (Ph.D.)--Columbia University, 2017.

Includes bibliographical references

Amyloid plaques, a neuropathological hallmark of Alzheimer's disease (AD), are largely composed of amyloid beta (Abeta) peptide, derived from cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase. The endosome is increasingly recognized as an important crossroads for APP and the secretases, with major implications for APP processing and amyloidogenesis. Amongst various posttranslational modifications affecting APP, ubiquitination of cytodomain lysines may represent a key signal controlling endosomal sorting. Here, we show that substitution of APP COOH-terminal lysines with arginines disrupts APP ubiquitination, though the pool of ubiquitinated APP is small or transient. Nonetheless, this small deficiency in ubiquitination can have a significant impact on APP, such that the number of lysines mutated trends toward an increase in APP metabolism. An APP mutant lacking all COOH-terminal lysines undergoes the most pronounced increase in processing, leading to accumulation of both secreted and intracellular Abeta40, without change in Abeta42. This phenotype is abolished by artificial ubiquitination of APP using rapalog-mediated proximity inducers. Lack of APP COOH-terminal lysines does not affect APP endocytosis, but leads to a redistribution of APP from endosomal intraluminal vesicles (ILVs) to the endosomal limiting membrane, with subsequent decrease in APP COOH-terminal fragment (CTF) content of secreted exosomes, but minimal effects on APP lysosomal degradation. Both the secreted and intracellular increase in Abeta40 is abolished by depletion of presenilin 2 (PSEN2), recently shown to be enriched on the endosomal limiting membrane compared to presenilin 1 (PSEN1). In a separate set of studies, we found that a familial AD mutant, L723P, which occurs immediately next to a string of three lysines in the juxtamembrane region, behaves more similarly to other FAD-causing mutations. APP L723P exhibits a selective increase in Abeta42, and a delay in degradation, but no change in exosomal content, despite some missorting to the endosomal limiting membrane. Our findings demonstrate that ubiquitin can act as a signal for endosomal sorting at five lysines in the APP cytodomain, disruption of which prevents sequestration of APP in ILVs and results in the processing of a larger pool of APP-CTF by PSEN2 on the endosomal membrane.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2018

Mode of access: World Wide Web

ISBN: 9781369535532Subjects--Topical Terms:

593561
Neurosciences.
Index Terms--Genre/Form:

554714
Electronic books.

Investigating the role of ubiquitin in endosomal sorting and processing of amyloid precursor protein.
LDR:03648ntm a2200349Ki 4500 001 918775
005 20181106104110.5
006 m o u
007 cr mn||||a|a||
008 190606s2017 xx obm 000 0 eng d
020 $a 9781369535532
035 $a (MiAaPQ)AAI10254140
035 $a (MiAaPQ)columbia:13717
035 $a AAI10254140
040 $a MiAaPQ $b eng $c MiAaPQ $d NTU
100 1 $a Williamson, Rebecca. $3 1193190
245 1 0 $a Investigating the role of ubiquitin in endosomal sorting and processing of amyloid precursor protein.
264 0 $c 2017
300 $a 1 online resource (151 pages)
336 $a text $b txt $2 rdacontent
337 $a computer $b c $2 rdamedia
338 $a online resource $b cr $2 rdacarrier
500 $a Source: Dissertation Abstracts International, Volume: 78-06(E), Section: B.
500 $a Adviser: Gilbert Di Paolo.
502 $a Thesis (Ph.D.)--Columbia University, 2017.
504 $a Includes bibliographical references
520 $a Amyloid plaques, a neuropathological hallmark of Alzheimer's disease (AD), are largely composed of amyloid beta (Abeta) peptide, derived from cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase. The endosome is increasingly recognized as an important crossroads for APP and the secretases, with major implications for APP processing and amyloidogenesis. Amongst various posttranslational modifications affecting APP, ubiquitination of cytodomain lysines may represent a key signal controlling endosomal sorting. Here, we show that substitution of APP COOH-terminal lysines with arginines disrupts APP ubiquitination, though the pool of ubiquitinated APP is small or transient. Nonetheless, this small deficiency in ubiquitination can have a significant impact on APP, such that the number of lysines mutated trends toward an increase in APP metabolism. An APP mutant lacking all COOH-terminal lysines undergoes the most pronounced increase in processing, leading to accumulation of both secreted and intracellular Abeta40, without change in Abeta42. This phenotype is abolished by artificial ubiquitination of APP using rapalog-mediated proximity inducers. Lack of APP COOH-terminal lysines does not affect APP endocytosis, but leads to a redistribution of APP from endosomal intraluminal vesicles (ILVs) to the endosomal limiting membrane, with subsequent decrease in APP COOH-terminal fragment (CTF) content of secreted exosomes, but minimal effects on APP lysosomal degradation. Both the secreted and intracellular increase in Abeta40 is abolished by depletion of presenilin 2 (PSEN2), recently shown to be enriched on the endosomal limiting membrane compared to presenilin 1 (PSEN1). In a separate set of studies, we found that a familial AD mutant, L723P, which occurs immediately next to a string of three lysines in the juxtamembrane region, behaves more similarly to other FAD-causing mutations. APP L723P exhibits a selective increase in Abeta42, and a delay in degradation, but no change in exosomal content, despite some missorting to the endosomal limiting membrane. Our findings demonstrate that ubiquitin can act as a signal for endosomal sorting at five lysines in the APP cytodomain, disruption of which prevents sequestration of APP in ILVs and results in the processing of a larger pool of APP-CTF by PSEN2 on the endosomal membrane.
533 $a Electronic reproduction. $b Ann Arbor, Mich. : $c ProQuest, $d 2018
538 $a Mode of access: World Wide Web
650 4 $a Neurosciences. $3 593561
650 4 $a Pathology. $3 668553
650 4 $a Molecular biology. $3 583443
655 7 $a Electronic books. $2 local $3 554714
690 $a 0317
690 $a 0571
690 $a 0307
710 2 $a ProQuest Information and Learning Co. $3 1178819
710 2 $a Columbia University. $b Neurobiology and Behavior. $3 1186904
773 0 $t Dissertation Abstracts International $g 78-06B(E).
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10254140 $z click for full text (PQDT)