Structure nor stability of the transmembrane spanning 6/7 domain of presenilin I correlates with pathogenicity.
Since its cloning in 1995, missense point mutations in presenilin I (PS-I) have been shown to be responsible for greater than 70% of the cases of early onset familial Alzheimer's disease (EOFAD), which can affect individuals as early as age 18. PS-I is known to be a component of gamma-secretase, the enzyme responsible for cleavage of the amyloid precursor protein (APP) into 42 amino acid peptides that aggregate to form the plaques surrounding neurons of Alzheimer's patients. It has recently been hypothesized that wild-type (wt) PS-I contains an autoinhibitory module that prevents gamma-secretase cleavage of the APP, while pathogenic PS-I point mutants lack a structure necessary for this inhibition. In this work, spectroscopic data is presented that does not correlate structure or stability of the proposed PS-I autoinhibitory module with pathogenicity.
Jeppesen
Brian
B
Department of Chemistry, Western Washington University, Bellingham, WA 98225-9150, USA.
Costello
Laura
L
Fung
Adam
A
Stanley
Erin
E
McDonald
Jessica
J
Lambert
Abbie
A
Johnson
Bennett
B
Gentile
Lisa
L
D000544:Alzheimer Disease / Q000235:genetics*; D002462:Cell Membrane / Q000737:chemistry; D006358:Hot Temperature; D006801:Humans; D017354:Point Mutation; D053764:Presenilin-1 / Q000737:chemistry* / Q000235:genetics; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013050:Spectrometry, Fluorescence
D053764:Presenilin-1