Presenilin-1 influences processing of the acetylcholinesterase membrane anchor PRiMA
Por:
Garcia-Ayllon, MS, Campanari, ML, Montenegro, MF, Cuchillo-Ibanez, I, Belbin, O, Lleo, A, Tsim, K, Vidal, CJ, Saez-Valero, J
Publicada:
1 jul 2014
Resumen:
Presenilin-1 (PS1) is the catalytic component of the gamma-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 (G(4)) 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 gamma-secretase inhibitor N-[ N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester have enabled us to study whether, through its g-secretase activity, PS1 participates in the processing of PRiMA-linked AChE. gamma-Secretase inhibition led to a notable increase in the level of PRiMAlinked AChE, suggesting that gamma-secretase is involved in the cleavage of PRiMA. We demonstrate that cleavage of PRiMA by gamma-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. (C) 2014 Elsevier Inc. All rights reserved.
Filiaciones:
Garcia-Ayllon, MS:
Univ Miguel Hernandez, CSIC, Inst Neurociencias Alicante, E-03550 Sant Joan dAlacant, Spain
Cetr Invest Biomed Red Enfermedades Neurodegenera, Madrid, Spain
Hosp Gen Univ Elche, Fdn Fomento Invest Sanitaria & Biomed Comunitat V, Unidad Invest, Elche, Spain
Campanari, ML:
Univ Miguel Hernandez, CSIC, Inst Neurociencias Alicante, E-03550 Sant Joan dAlacant, Spain
Cetr Invest Biomed Red Enfermedades Neurodegenera, Madrid, Spain
Montenegro, MF:
Univ Murcia, Dept Bioquim & Biol Mol A, Murcia, Spain
Cuchillo-Ibanez, I:
Univ Miguel Hernandez, CSIC, Inst Neurociencias Alicante, E-03550 Sant Joan dAlacant, Spain
Cetr Invest Biomed Red Enfermedades Neurodegenera, Madrid, Spain
Belbin, O:
Hosp Santa Creu & Sant Pau, Dept Neurol, Memory Unit, Barcelona, Spain
Lleo, A:
Cetr Invest Biomed Red Enfermedades Neurodegenera, Madrid, Spain
Hosp Santa Creu & Sant Pau, Dept Neurol, Memory Unit, Barcelona, Spain
Tsim, K:
Hong Kong Univ Sci & Technol, Div Life Sci, Hong Kong, Hong Kong, Peoples R China
Hong Kong Univ Sci & Technol, Ctr Chinese Med, Hong Kong, Hong Kong, Peoples R China
Vidal, CJ:
Univ Murcia, Dept Bioquim & Biol Mol A, Murcia, Spain
Saez-Valero, J:
Univ Miguel Hernandez, CSIC, Inst Neurociencias Alicante, E-03550 Sant Joan dAlacant, Spain
Cetr Invest Biomed Red Enfermedades Neurodegenera, Madrid, Spain
Open Access
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