| First Author | Ben-Gedalya T | Year | 2015 |
| Journal | EMBO J | Volume | 34 |
| Issue | 22 | Pages | 2820-39 |
| PubMed ID | 26438723 | Mgi Jnum | J:227775 |
| Mgi Id | MGI:5702795 | Doi | 10.15252/embj.201592042 |
| Citation | Ben-Gedalya T, et al. (2015) Alzheimer's disease-causing proline substitutions lead to presenilin 1 aggregation and malfunction. EMBO J 34(22):2820-39 |
| abstractText | 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. |
