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Alzheimer's disease‐causing proline substitutions lead to presenilin 1 aggregation and malfunction
Author(s) -
BenGedalya Tziona,
Moll Lorna,
BejeranoSagie Michal,
Frere Samuel,
Cabral Wayne A,
FriedmannMorvinski Dinorah,
Slutsky Inna,
BurstynCohen Tal,
Marini Joan C,
Cohen Ehud
Publication year - 2015
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201592042
Subject(s) - neurodegeneration , presenilin , biology , cyclophilin , chaperone (clinical) , microbiology and biotechnology , endoplasmic reticulum , protein folding , alzheimer's disease , disease , genetics , neuroscience , gene , medicine , pathology
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.