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Alzheimer's disease-causing proline substitutions lead to presenilin 1 aggregation and malfunction.


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 ?-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.

SUBMITTER: Ben-Gedalya T 

PROVIDER: S-EPMC4682640 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Alzheimer's disease-causing proline substitutions lead to presenilin 1 aggregation and malfunction.

Ben-Gedalya Tziona T   Moll Lorna L   Bejerano-Sagie Michal M   Frere Samuel S   Cabral Wayne A WA   Friedmann-Morvinski Dinorah D   Slutsky Inna I   Burstyn-Cohen Tal T   Marini Joan C JC   Cohen Ehud E  

The EMBO journal 20151005 22


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 pr  ...[more]

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