Elucidation of the BACE1 Regulating Factor GGA3 in Alzheimer's Disease

Article type: Research Article

Authors: Natunen, Teemu^a | Parrado, Antonio R.^b | Helisalmi, Seppo^a | Pursiheimo, Juha-Pekka^c | Sarajärvi, Timo^a | Mäkinen, Petra^a | Kurkinen, Kaisa M.A.^a | Mullin, Kristina^b | Alafuzoff, Irina^d | Haapasalo, Annakaisa^a | Bertram, Lars^e | Soininen, Hilkka^{a; f} | Tanzi, Rudolph E.^b | Hiltunen, Mikko^{a; *}

Affiliations: [a] Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, Finland | [b] Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, and Harvard Medical School, Boston, MA, USA | [c] Turku Centre for Biotechnology, University of Turku, Turku, Finland | [d] Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden | [e] Neuropsychiatric Genetics Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany | [f] Department of Neurology, Kuopio University Hospital, Kuopio, Finland

Correspondence: [*] Correspondence to: Mikko Hiltunen, PhD, Institute of Clinical Medicine-Neurology, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland. Tel.: +358 40 3552014; Fax: +358 17 162048; E-mail: mikko.hiltunen@uef.fi.

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.

Keywords: Alzheimer's disease, amyloid-β, β-secretase, Braak staging, eukaryotic translation initiation factor 2α, frozen brain tissue samples, Golgi-localized γ-ear-containing ADP-ribosylation factor-binding protein, polymorphism, protein stability, tau protein

DOI: 10.3233/JAD-130104

Journal: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 217-232, 2013