title: Elucidation of the BACE1 regulating factor GGA3 in Alzheimer's disease.
abstract: Golgi-localized γ-ear-containing ADP-ribosylation factor-binding protein (GGA3) is a central regulator of trafficking and degradation of BACE1 (β-site AβPP-cleaving enzyme), the rate-limiting enzyme in the production of amyloid-β (Aβ) in Alzheimer's disease (AD). Here, we assessed the potential role of GGA3 in AD pathogenesis using independent neuropathological, case-control, and family-based human sample cohorts. Increased BACE1 levels coincided with decreased GGA3 levels and with elevated phosphorylation status of eIF2α-Ser51 in the temporal cortex of AD patients as compared to age-matched controls. Severity of the disease did not alter mRNA or protein levels of GGA3 in the inferior temporal cortex of AD patients, while a positive correlation between GGA3 and the levels of total, but not phosphorylated, tau was observed. Genetically, we did not observe consistent evidence for association between AD risk and common GGA3 polymorphisms across a number of independent sample cohorts. However, a nominally significant association was observed with rs2242230 (p < 0.05) among the Finnish case-control cohort. Accordingly, mRNA and protein levels of GGA3 in the inferior temporal cortex of AD patients did not significantly correlate with rs2242230 genotype status. While the present study indicates that GGA3 is involved in the cellular processes relevant for AD pathogenesis, the genetic data do not support the idea that common GGA3 polymorphisms would contribute to AD risk.
authors: Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland.
authors: Teemu
authors: T
authors: Natunen
authors: Antonio R
authors: AR
authors: Parrado
authors: Seppo
authors: S
authors: Helisalmi
authors: Juha-Pekka
authors: JP
authors: Pursiheimo
authors: Timo
authors: T
authors: Sarajärvi
authors: Petra
authors: P
authors: Mäkinen
authors: Kaisa M A
authors: KM
authors: Kurkinen
authors: Kristina
authors: K
authors: Mullin
authors: Irina
authors: I
authors: Alafuzoff
authors: Annakaisa
authors: A
authors: Haapasalo
authors: Lars
authors: L
authors: Bertram
authors: Hilkka
authors: H
authors: Soininen
authors: Rudolph E
authors: RE
authors: Tanzi
authors: Mikko
authors: M
authors: Hiltunen
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000096:biosynthesis* / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis* / Q000235:genetics; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013702:Temporal Lobe / Q000378:metabolism* / Q000473:pathology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C407306:GGA adaptor proteins; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human