Monoamine oxidase-A physically interacts with presenilin-1(M146V) in the mouse cortex.
J Alzheimers Dis
; 28(2): 403-22, 2012.
Article
em En
| MEDLINE
| ID: mdl-22045496
ABSTRACT
The concentration of presenilin-1 (PS-1) protein at the mitochondrial-associated aspect of the endoplasmic reticulum supports the potential for a mitochondrial influence of PS-1. Given that carriers of certain Alzheimer's disease (AD)-related PS-1 variants are predisposed to clinical depression and that depression has been historically associated with the mitochondrial enzyme, monoamine oxidase-A (MAO-A), we investigated cortical MAO-A function in the AD-related PS-1(M146V) knock-in mouse. The MAO-A system was clearly altered in the PS-1(M146V) mouse as revealed by (a) a mismatch between MAO-A protein expression and MAO-A activity; (b) changes in MAO-A-mediated monoaminergic neurotransmitter metabolism; (c) changes in non-cognitive behavior following treatment with the irreversible MAO-A inhibitor clorgyline; and (d) an increase in the potency of clorgyline in these same mice. We next investigated whether PS-1(M146V) could be influencing MAO-A directly. We observed (a) an enhanced MAO-A activity in necropsied PS-1(M146V) mouse cortical extracts incubated with DAPT (a PS-1 substrate-competitor); (b) the proximity of PS-1 with MAO-A and mitochondrial markers in cortical sections and in primary cortical neurons; (c) the co-segregation and co-immunoprecipitation of PS-1 and MAO-A within the mitochondrial fraction; and (d) the co-immunoprecipitation of overexpressed PS-1(M146V) and MAO-A proteins from N2a lysates. The PS-1(ΔEx9) and PS-1(D257A) variants, known to have low substrate-binding capacity, co-immunoprecipitated weakly with MAO-A. These combined data support a physical interaction between PS-1 and MAO-A that could influence MAO-A activity and contribute to the monoaminergic disruptions common to disorders as seemingly diverse as depression and AD.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Valina
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Regulação Enzimológica da Expressão Gênica
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Córtex Cerebral
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Presenilina-1
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Doença de Alzheimer
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Metionina
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Monoaminoxidase
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article