Presenilin-1 influences processing of the acetylcholinesterase membrane anchor PRiMA
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)....
| Autores: | , , , , , , , , |
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| Tipo de documento: | artigo |
| Estado: | Versión aceptada para publicación |
| Data de publicação: | 2014 |
| País: | España |
| Recursos: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositório: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/103460 |
| Acesso em linha: | http://hdl.handle.net/10261/103460 |
| Access Level: | Acceso aberto |
| Palavra-chave: | Acetylcholinesterase PRiMA Presenilin 1 γ-Secretase Alzheimer's disease |
| Resumo: | 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. © 2014 Elsevier Inc. |
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