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http://hdl.handle.net/2445/68205
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DC Field | Value | Language |
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dc.contributor.author | Sepulveda Falla, Diego | - |
dc.contributor.author | Barrera Ocampo, Alvaro | - |
dc.contributor.author | Hagel, Christian | - |
dc.contributor.author | Korwitz, Anne | - |
dc.contributor.author | Vinueza Veloz, María Fernanda | - |
dc.contributor.author | Zhou, Kuikui | - |
dc.contributor.author | Schonewille, Martijn | - |
dc.contributor.author | Zhou, Haibo | - |
dc.contributor.author | Velázquez Pérez, Luis | - |
dc.contributor.author | Rodríguez Labrada, Roberto | - |
dc.contributor.author | Villegas, Andrés | - |
dc.contributor.author | Ferrer, Isidro (Ferrer Abizanda) | - |
dc.contributor.author | Lopera, Francisco | - |
dc.contributor.author | Langer, Thomas | - |
dc.contributor.author | De Zeeuw, Chris I. | - |
dc.contributor.author | Glatzel, Markus | - |
dc.date.accessioned | 2015-11-30T16:31:21Z | - |
dc.date.available | 2015-11-30T16:31:21Z | - |
dc.date.issued | 2014-04-01 | - |
dc.identifier.issn | 0021-9738 | - |
dc.identifier.uri | http://hdl.handle.net/2445/68205 | - |
dc.description.abstract | Familial Alzheimer's disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred carrying the PS1-E280A mutation is the largest known cohort of PS1-FAD patients. Here, we investigated PS1-E280A-associated cerebellar dysfunction and found that it occurs early in PS1-E208A carriers, while cerebellar signs are highly prevalent in patients with dementia. Postmortem analysis of cerebella of PS1-E280A carrier revealed greater Purkinje cell (PC) loss and more abnormal mitochondria compared with controls. In PS1-E280A tissue, ER/mitochondria tethering was impaired, Ca2+ channels IP3Rs and CACNA1A were downregulated, and Ca2+-dependent mitochondrial transport proteins MIRO1 and KIF5C were reduced. Accordingly, expression of PS1-E280A in a neuronal cell line altered ER/mitochondria tethering and transport compared with that in cells expressing wild-type PS1. In a murine model of PS1-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar β-amyloid deposition. Our data suggest that impaired calcium homeostasis and mitochondrial dysfunction in PS1-FAD PCs reduces their activity and contributes to motor coordination deficits prior to Aβ aggregation and dementia. We propose that PS1-E280A affects both Ca2+ homeostasis and Aβ precursor processing, leading to FAD and neurodegeneration. | - |
dc.format.extent | 16 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | American Society for Clinical Investigation | - |
dc.relation.isformatof | Reproducció del document publicat a: http://dx.doi.org/10.1172/JCI66407 | - |
dc.relation.ispartof | Journal of Clinical Investigation, 2014, vol. 124, num. 4, p. 1552-1567 | - |
dc.relation.uri | http://dx.doi.org/10.1172/JCI66407 | - |
dc.rights | (c) American Society for Clinical Investigation, 2014 | - |
dc.source | Articles publicats en revistes (Patologia i Terapèutica Experimental) | - |
dc.subject.classification | Malaltia d'Alzheimer | - |
dc.subject.classification | Homeòstasi | - |
dc.subject.classification | Cervell | - |
dc.subject.other | Alzheimer's disease | - |
dc.subject.other | Homeostasis | - |
dc.subject.other | Brain | - |
dc.title | Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.identifier.idgrec | 647647 | - |
dc.date.updated | 2015-11-30T16:31:21Z | - |
dc.relation.projectID | info:eu-repo/grantAgreement/EC/FP7/294775/EU//CCC | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 24569455 | - |
Appears in Collections: | Articles publicats en revistes (Patologia i Terapèutica Experimental) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
Files in This Item:
File | Description | Size | Format | |
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647647.pdf | 8.39 MB | Adobe PDF | View/Open |
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