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

作者：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^*

来源：The EMBO Journal, 2015, 34(22): 2820-2839.

DOI：10.15252/embj.201592042

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

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 gamma-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.

• 出版日期2015-11-12