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

Tziona Ben-Gedalya, Lorna Moll, Michal Bejerano-Sagie, Samuel Frere, Wayne A. Cabral, Dinorah Friedmann-Morvinski, Inna Slutsky, Tal Burstyn-Cohen, Joan C. Marini, Ehud Cohen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


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.

Original languageAmerican English
Pages (from-to)2820-2839
Number of pages20
JournalEMBO Journal
Issue number22
StatePublished - 12 Nov 2015

Bibliographical note

Publisher Copyright:
© 2015 The Authors.


  • Alzheimer's disease
  • cyclophilin B
  • presenilin 1
  • proteostasis


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