Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease
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...When these two phenomena (inhibition of presenilin endoproteolysis and of g-secretase cleavage) were examined together by placing an aspartate-to-alanine mutation in the natural variant of presenilin that lacks exon 9 (and therefore the site for PS1 endoproteolytic cleavage), this mutant holoprotein still abrogated g-secretase cleavage of APP (188)....
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...Deletion of just one PS1 gene in the mouse has not been associated with any major phenotypic abnormalities to date....
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...Examination of Ire1 processing in cells derived from PS1 knockout mice suggested that presenilin is required for proper cleavage of Ire1, putatively within its single transmembrane domain (106)....
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...Interestingly, stable expression of the TM aspartate to alanine mutations in both PS1 and PS2 in the same cell decreases Ab production to undetectable levels, suggesting an absolute requirement for functional presenilins (and their TM aspartates in particular) to generate any Ab (74)....
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...Shortly after the PS1 and PS2 genes were cloned and missense mutations within them shown to cause autosomal dominant AD, two important observations about their biology were made....
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