Presenilin-1 influences processing of the acetylcholinesterase membrane anchor PRiMA

• Published in: Neurobiology of aging Vol. 35; no. 7; pp. 1526 - 1536
• Main Authors: García-Ayllón, María-Salud, Campanari, María-Letizia, Montenegro, María-Fernanda, Cuchillo-Ibáñez, Inmaculada, Belbin, Olivia, Lleó, Alberto, Tsim, Karl, Vidal, Cecilio J., Sáez-Valero, Javier
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2014
• Subjects: Acetylcholinesterase; Acetylcholinesterase - metabolism; Acetylcholinesterase - physiology; Acetylcholinesterase - therapeutic use; Alzheimer Disease - drug therapy; Alzheimer Disease - etiology; Alzheimer's disease; Amyloid Precursor Protein Secretases - physiology; Amyloid Precursor Protein Secretases - therapeutic use; Animals; Brain - enzymology; Brain - metabolism; Cell Nucleus - enzymology; Cells, Cultured; Cricetinae; Drug Design; Female; Gene Expression - genetics; Internal Medicine; Membrane Microdomains - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Knockout; Molecular Targeted Therapy; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurology; Presenilin 1; Presenilin-1 - physiology; PRiMA; γ-Secretase; Acetylcholinesterase; Presenilin 1; PRiMA; Alzheimer's disease; γ-Secretase
• ISSN: 0197-4580; 1558-1497; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2014.01.147

Presenilin-1 (PS1) is the catalytic component of the γ-secretase complex. In this study, we explore if PS1 participates in the processing of the cholinergic acetylcholinesterase (AChE). The major AChE variant expressed in the brain is a tetramer (G4) bound to a proline-rich membrane anchor (PRiMA). Overexpression of the transmembrane PRiMA protein in Chinese hamster ovary cells expressing AChE and treated with the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester have enabled us to study whether, through its γ-secretase activity, PS1 participates in the processing of PRiMA-linked AChE. γ-Secretase inhibition led to a notable increase in the level of PRiMA-linked AChE, suggesting that γ-secretase is involved in the cleavage of PRiMA. We demonstrate that cleavage of PRiMA by γ-secretase results in a C-terminal PRiMA fragment. Immunofluorescence labeling allowed us to identify this PRiMA fragment in the nucleus. Moreover, we have determined changes in the proportion of the raft-residing AChE-PRiMA in a PS1 conditional knockout mouse. Our results are of interest as both enzymes have therapeutic relevance for Alzheimer's disease.