Alzheimer's disease-causing proline substitutions lead to presenilin 1 aggregation and malfunction.
EMBO J
; 34(22): 2820-39, 2015 Nov 12.
Article
em En
| MEDLINE
| ID: mdl-26438723
ABSTRACT
Do different neurodegenerative maladies emanate from the failure of a mutual protein folding mechanism? We have addressed this question by comparing mutational patterns that are linked to the manifestation of distinct neurodegenerative disorders and identified similar neurodegeneration-linked proline substitutions in the prion protein and in presenilin 1 that underlie the development of a prion disorder and of familial Alzheimer's disease (fAD), respectively. These substitutions were found to prevent the endoplasmic reticulum (ER)-resident chaperone, cyclophilin B, from assisting presenilin 1 to fold properly, leading to its aggregation, deposition in the ER, reduction of γ-secretase activity, and impaired mitochondrial distribution and function. Similarly, reduced quantities of the processed, active presenilin 1 were observed in brains of cyclophilin B knockout mice. These discoveries imply that reduced cyclophilin activity contributes to the development of distinct neurodegenerative disorders, propose a novel mechanism for the development of certain fAD cases, and support the emerging theme that this disorder can stem from aberrant presenilin 1 function. This study also points at ER chaperones as targets for the development of counter-neurodegeneration therapies.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Encéfalo
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Substituição de Aminoácidos
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Presenilina-1
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Doença de Alzheimer
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Agregação Patológica de Proteínas
Limite:
Animals
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article