DISC1 regulates trafficking and processing of APP and Aβ generation

We report the novel regulation of proteolytic processing of amyloid precursor protein (APP) by DISC1, a major risk factor for psychiatric illnesses, such as depression and schizophrenia. RNAi-knockdown of DISC1 in mature primary cortical neurons led to a significant increase in the levels of intrace...

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Main Authors:	Shahani, Neelam, Seshadri, Saurav, Jaaro-Peled, Hanna, Ishizuka, Koko, Hirota-Tsuyada, Yuki, Wang, Qi, Koga, Minori, Sedlak, Thomas W., Korth, Carsten, Brandon, Nicholas J., Kamiya, Atsushi, Subramaniam, Srinivasa, Tomoda, Toshifumi, Sawa, Akira
Format:	Online
Language:	English
Published:	2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362789/

id	pubmed-4362789
recordtype	oai_dc
spelling	pubmed-43627892016-01-01 DISC1 regulates trafficking and processing of APP and Aβ generation Shahani, Neelam Seshadri, Saurav Jaaro-Peled, Hanna Ishizuka, Koko Hirota-Tsuyada, Yuki Wang, Qi Koga, Minori Sedlak, Thomas W. Korth, Carsten Brandon, Nicholas J. Kamiya, Atsushi Subramaniam, Srinivasa Tomoda, Toshifumi Sawa, Akira Article We report the novel regulation of proteolytic processing of amyloid precursor protein (APP) by DISC1, a major risk factor for psychiatric illnesses, such as depression and schizophrenia. RNAi-knockdown of DISC1 in mature primary cortical neurons led to a significant increase in the levels of intracellular α-C-terminal fragment of APP (APP-CTFα) and the corresponding N-terminal secreted ectodomain product sAPPα. DISC1 knockdown also elicited a significant decrease in the levels of Aβ42 and Aβ40. These aberrant proteolytic events were successfully rescued by co-expression of wild-type DISC1, but not by mutant DISC1 lacking the amino acids required for the interaction with APP, suggesting that APP-DISC1 protein interactions are crucial for the regulation of the C-terminal proteolysis. In a genetically-engineered model in which a major full-length DISC1 isoform is depleted, consistent changes in APP processing were seen: an increase in APP-CTFα and decrease in Aβ42 and Aβ40 levels. Finally we found that knockdown of DISC1 increased the expression of APP at the cell surface and decreased its internalization. The presented DISC1 mechanism of APP proteolytic processing and Aβ peptide generation, which is central to Alzheimer’s disease pathology, suggests a novel interface between neurological and psychiatric conditions. 2014-09-16 2015-07 /pmc/articles/PMC4362789/ /pubmed/25224257 http://dx.doi.org/10.1038/mp.2014.100 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Shahani, Neelam Seshadri, Saurav Jaaro-Peled, Hanna Ishizuka, Koko Hirota-Tsuyada, Yuki Wang, Qi Koga, Minori Sedlak, Thomas W. Korth, Carsten Brandon, Nicholas J. Kamiya, Atsushi Subramaniam, Srinivasa Tomoda, Toshifumi Sawa, Akira
spellingShingle	Shahani, Neelam Seshadri, Saurav Jaaro-Peled, Hanna Ishizuka, Koko Hirota-Tsuyada, Yuki Wang, Qi Koga, Minori Sedlak, Thomas W. Korth, Carsten Brandon, Nicholas J. Kamiya, Atsushi Subramaniam, Srinivasa Tomoda, Toshifumi Sawa, Akira DISC1 regulates trafficking and processing of APP and Aβ generation
author_facet	Shahani, Neelam Seshadri, Saurav Jaaro-Peled, Hanna Ishizuka, Koko Hirota-Tsuyada, Yuki Wang, Qi Koga, Minori Sedlak, Thomas W. Korth, Carsten Brandon, Nicholas J. Kamiya, Atsushi Subramaniam, Srinivasa Tomoda, Toshifumi Sawa, Akira
author_sort	Shahani, Neelam
title	DISC1 regulates trafficking and processing of APP and Aβ generation
title_short	DISC1 regulates trafficking and processing of APP and Aβ generation
title_full	DISC1 regulates trafficking and processing of APP and Aβ generation
title_fullStr	DISC1 regulates trafficking and processing of APP and Aβ generation
title_full_unstemmed	DISC1 regulates trafficking and processing of APP and Aβ generation
title_sort	disc1 regulates trafficking and processing of app and aβ generation
description	We report the novel regulation of proteolytic processing of amyloid precursor protein (APP) by DISC1, a major risk factor for psychiatric illnesses, such as depression and schizophrenia. RNAi-knockdown of DISC1 in mature primary cortical neurons led to a significant increase in the levels of intracellular α-C-terminal fragment of APP (APP-CTFα) and the corresponding N-terminal secreted ectodomain product sAPPα. DISC1 knockdown also elicited a significant decrease in the levels of Aβ42 and Aβ40. These aberrant proteolytic events were successfully rescued by co-expression of wild-type DISC1, but not by mutant DISC1 lacking the amino acids required for the interaction with APP, suggesting that APP-DISC1 protein interactions are crucial for the regulation of the C-terminal proteolysis. In a genetically-engineered model in which a major full-length DISC1 isoform is depleted, consistent changes in APP processing were seen: an increase in APP-CTFα and decrease in Aβ42 and Aβ40 levels. Finally we found that knockdown of DISC1 increased the expression of APP at the cell surface and decreased its internalization. The presented DISC1 mechanism of APP proteolytic processing and Aβ peptide generation, which is central to Alzheimer’s disease pathology, suggests a novel interface between neurological and psychiatric conditions.
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362789/
_version_	1613199703251353600

DISC1 regulates trafficking and processing of APP and Aβ generation

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