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PMID:24577224

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Citation

Kanatsu, K, Morohashi, Y, Suzuki, M, Kuroda, H, Watanabe, T, Tomita, T and Iwatsubo, T (2014) Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase. Nat Commun 5:3386

Abstract

A body of evidence suggests that aberrant metabolism of amyloid-β peptide (Aβ) underlies the aetiology of Alzheimer disease (AD). Recently, a single-nucleotide polymorphism in phosphatidylinositol binding clathrin assembly protein (PICALM/CALM) gene, which encodes a protein implicated in the clathrin-mediated endocytosis, was identified as a genetic protective factor for AD, although its mechanistic details have little been explored. Here we show that loss of CALM leads to the selective decrease in the production ratio of the pathogenic Aβ species, Aβ42. Active form of γ-secretase is constitutively endocytosed via the clathrin-mediated pathway in a CALM dependent manner. Alteration in the rate of clathrin-mediated endocytosis of γ-secretase causes a shift in its steady-state localization, which consequently impacts on the production ratio of Aβ42. Our study identifies CALM as an endogenous modulator of γ-secretase activity by regulating its endocytosis and also as an excellent target for Aβ42-lowering AD therapeutics.

Links

PubMed Online version:10.1038/ncomms4386

Keywords

Amyloid Precursor Protein Secretases/genetics; Amyloid Precursor Protein Secretases/metabolism; Amyloid beta-Peptides/genetics; Amyloid beta-Peptides/metabolism; Animals; Endocytosis/genetics; Endocytosis/physiology; Female; HeLa Cells; Humans; Mice; Mice, Mutant Strains; Monomeric Clathrin Assembly Proteins/genetics; Monomeric Clathrin Assembly Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:PICAL

involved_in

GO:1902004: positive regulation of amyloid-beta formation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PICAL

involved_in

GO:0035459: vesicle cargo loading

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PICAL

involved_in

GO:0072583: clathrin-dependent endocytosis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PICAL

involved_in

GO:1902004: positive regulation of amyloid-beta formation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PICAL

involved_in

GO:1902959: regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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Internal error

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[f4496c6f13bd3aaf648dbe99] /wiki/index.php/PMID:24577224 Error from line 252 of /usr/local/github/wiki-extensions/wiki-extensions-hulab/AnnotationLinks/AnnotationLinks.php: Call to a member function getIdentifier() on null

Backtrace:

#0 /usr/local/github/wiki-extensions/wiki-extensions-hulab/AnnotationLinks/AnnotationLinks.php(70): AnnotationLinks::getQuickGOannotations(string, array)
#1 /var/www/html/go/wiki/includes/parser/Parser.php(3888): AnnotationLinks::renderAnnotations(NULL, array, Parser, PPFrame_DOM)
#2 /var/www/html/go/wiki/includes/parser/Preprocessor_DOM.php(1362): Parser->extensionSubstitution(array, PPFrame_DOM)
#3 /var/www/html/go/wiki/includes/parser/Parser.php(2942): PPFrame_DOM->expand(DOMElement, integer)
#4 /var/www/html/go/wiki/includes/parser/Parser.php(1293): Parser->replaceVariables(string)
#5 /var/www/html/go/wiki/includes/parser/Parser.php(443): Parser->internalParse(string)
#6 /var/www/html/go/wiki/includes/content/WikitextContent.php(323): Parser->parse(string, Title, ParserOptions, boolean, boolean, integer)
#7 /var/www/html/go/wiki/includes/content/AbstractContent.php(516): WikitextContent->fillParserOutput(Title, integer, ParserOptions, boolean, ParserOutput)
#8 /var/www/html/go/wiki/includes/jobqueue/jobs/RefreshLinksJob.php(231): AbstractContent->getParserOutput(Title, integer, ParserOptions, boolean)
#9 /var/www/html/go/wiki/includes/jobqueue/jobs/RefreshLinksJob.php(126): RefreshLinksJob->runForTitle(Title)
#10 /var/www/html/go/wiki/includes/jobqueue/JobRunner.php(296): RefreshLinksJob->run()
#11 /var/www/html/go/wiki/includes/jobqueue/JobRunner.php(193): JobRunner->executeJob(RefreshLinksJob, Wikimedia\Rdbms\LBFactorySimple, BufferingStatsdDataFactory, integer)
#12 /var/www/html/go/wiki/includes/MediaWiki.php(1002): JobRunner->run(array)
#13 /var/www/html/go/wiki/includes/MediaWiki.php(988): MediaWiki->triggerSyncJobs(integer, MediaWiki\Logger\LegacyLogger)
#14 /var/www/html/go/wiki/includes/MediaWiki.php(912): MediaWiki->triggerJobs()
#15 /var/www/html/go/wiki/includes/MediaWiki.php(727): MediaWiki->restInPeace(string, boolean)
#16 /var/www/html/go/wiki/includes/MediaWiki.php(750): MediaWiki->{closure}()
#17 /var/www/html/go/wiki/includes/MediaWiki.php(557): MediaWiki->doPostOutputShutdown(string)
#18 /var/www/html/go/wiki/index.php(42): MediaWiki->run()
#19 {main}

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