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

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Investigating the role of ubiquitin in endosomal sorting and processing of amyloid precursor protein./
Author:	Williamson, Rebecca.
Description:	1 online resource (151 pages)
Notes:	Source: Dissertation Abstracts International, Volume: 78-06(E), Section: B.
Contained By:	Dissertation Abstracts International78-06B(E).
Subject:	Neurosciences. -
Online resource:	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.
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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.
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