title: 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 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.
authors.affiliation: Biochemistry and Molecular Biology, The Institute for Medical Research Israel - Canada (IMRIC), The Hebrew University Medical School, Jerusalem, Israel.
authors.forename: Tziona
authors.initials: T
authors.lastname: Ben-Gedalya
authors.affiliation: Biochemistry and Molecular Biology, The Institute for Medical Research Israel - Canada (IMRIC), The Hebrew University Medical School, Jerusalem, Israel.
authors.forename: Lorna
authors.initials: L
authors.lastname: Moll
authors.affiliation: Biochemistry and Molecular Biology, The Institute for Medical Research Israel - Canada (IMRIC), The Hebrew University Medical School, Jerusalem, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Bejerano-Sagie
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Samuel
authors.initials: S
authors.lastname: Frere
authors.affiliation: Bone and Extracellular Matrix Branch, NICHD, NIH, Bethesda, MD, USA.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Cabral
authors.affiliation: Biochemistry and Molecular Biology, Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Dinorah
authors.initials: D
authors.lastname: Friedmann-Morvinski
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Inna
authors.initials: I
authors.lastname: Slutsky
authors.affiliation: Institute for Dental Sciences, Faculty of Dental Medicine Hebrew University - Hadassah, Jerusalem, Israel.
authors.forename: Tal
authors.initials: T
authors.lastname: Burstyn-Cohen
authors.affiliation: Bone and Extracellular Matrix Branch, NICHD, NIH, Bethesda, MD, USA.
authors.forename: Joan C
authors.initials: JC
authors.lastname: Marini
authors.affiliation: Biochemistry and Molecular Biology, The Institute for Medical Research Israel - Canada (IMRIC), The Hebrew University Medical School, Jerusalem, Israel ehudc@ekmd.huji.ac.il.
authors.forename: Ehud
authors.initials: E
authors.lastname: Cohen
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019943:Amino Acid Substitution; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D011392:Proline / Q000235:genetics / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017510:Protein Folding
chemical_list: D018832:Molecular Chaperones; D053764:Presenilin-1; C580804:presenilin 1, mouse; D011392:Proline
keywords: Alzheimer's disease; cyclophilin B; presenilin 1; proteostasis