Alzheimer's disease‐causing proline substitutions lead to presenilin 1 aggregation and malfunction. (5th October 2015)

• Record Type: Journal Article
• Authors: Ben‐Gedalya, Tziona; Moll, Lorna; Bejerano‐Sagie, Michal; Frere, Samuel; Cabral, Wayne A; Friedmann‐Morvinski, Dinorah; Slutsky, Inna; Burstyn‐Cohen, Tal; Marini, Joan C; Cohen, Ehud
• Is Part Of: EMBO journal. Volume 34:Number 22(2015)
• Page Start: 2820
• Page End: 2839
• Publication Date: 2015-10-05
• Subjects: Alzheimer's disease -- cyclophilin B -- presenilin 1 -- proteostasis; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201592042
• Languages: English
• ISSNs: 0261-4189

Abstract

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. Synopsis: Alzheimer's disease‐associated protein presenilin 1 requires cyclophilin B in order to fold and function properly. Familial Alzheimer's disease‐linked proline substitutions in presenilin 1 impair its functional interaction with cyclophilin B. Similar mutations in distinct proteins help decipher mechanisms of neurodegeneration. The inhibition of cyclophilins induces misfolding and degradation or aggregation of presenilin 1. Aggregated presenilin 1 accumulates in an ER‐derived quality control compartment. Proline substitutions in presenilin 1 attenuate γ‐secretase activity and impair mitochondrial distribution and function. Abstract : Proper presenilin 1 folding and aggregation prevention in vivo is found to require the ER chaperone cyclophilin B, whose action on presenilin 1 is impaired by familial Alzheimer's disease‐associated mutations in the latter.