Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/68205
Title: Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis
Author: Sepulveda Falla, Diego
Barrera Ocampo, Alvaro
Hagel, Christian
Korwitz, Anne
Vinueza Veloz, María Fernanda
Zhou, Kuikui
Schonewille, Martijn
Zhou, Haibo
Velázquez Pérez, Luis
Rodríguez Labrada, Roberto
Villegas, Andrés
Ferrer, Isidro (Ferrer Abizanda)
Lopera, Francisco
Langer, Thomas
De Zeeuw, Chris I.
Glatzel, Markus
Keywords: Malaltia d'Alzheimer
Homeòstasi
Cervell
Alzheimer's disease
Homeostasis
Brain
Issue Date: 1-Apr-2014
Publisher: American Society for Clinical Investigation
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.
Note: Reproducció del document publicat a: http://dx.doi.org/10.1172/JCI66407
It is part of: Journal of Clinical Investigation, 2014, vol. 124, num. 4, p. 1552-1567
Related resource: http://dx.doi.org/10.1172/JCI66407
URI: http://hdl.handle.net/2445/68205
ISSN: 0021-9738
Appears in Collections:Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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