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|Title:||Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis|
|Author:||Sepulveda Falla, Diego|
Barrera Ocampo, Alvaro
Vinueza Veloz, María Fernanda
Velázquez Pérez, Luis
Rodríguez Labrada, Roberto
Ferrer, Isidro (Ferrer Abizanda)
De Zeeuw, Chris I.
|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|
|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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