Sepulveda-Falla, Diego ORCID: 0000-0003-0176-2042, Barrera-Ocampo, Alvaro ORCID: 0000-0003-0906-9293, Hagel, Christian, Korwitz, Anne, Vinueza-Veloz, Maria Fernanda, Zhou, Kuikui, Schonewille, Martijn, Zhou, Haibo, Velazquez-Perez, Luis, Rodriguez-Labrada, Roberto ORCID: 0000-0003-3193-7683, Villegas, Andres, Ferrer, Isidro, Lopera, Francisco, Langer, Thomas ORCID: 0000-0003-1250-1462, De Zeeuw, Chris I. and Glatzel, Markus ORCID: 0000-0002-7720-8817 (2014). Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis. J. Clin. Invest., 124 (4). S. 1552 - 1568. ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 1558-8238

Full text not available from this repository.

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 PSI-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar beta-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 A beta aggregation and dementia. We propose that PS1-E280A affects both Ca2+ homeostasis and A beta precursor processing, leading to FAD and neurodegeneration.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Sepulveda-Falla, DiegoUNSPECIFIEDorcid.org/0000-0003-0176-2042UNSPECIFIED
Barrera-Ocampo, AlvaroUNSPECIFIEDorcid.org/0000-0003-0906-9293UNSPECIFIED
Hagel, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Korwitz, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vinueza-Veloz, Maria FernandaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhou, KuikuiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schonewille, MartijnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhou, HaiboUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Velazquez-Perez, LuisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodriguez-Labrada, RobertoUNSPECIFIEDorcid.org/0000-0003-3193-7683UNSPECIFIED
Villegas, AndresUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ferrer, IsidroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lopera, FranciscoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Langer, ThomasUNSPECIFIEDorcid.org/0000-0003-1250-1462UNSPECIFIED
De Zeeuw, Chris I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Glatzel, MarkusUNSPECIFIEDorcid.org/0000-0002-7720-8817UNSPECIFIED
URN: urn:nbn:de:hbz:38-442562
DOI: 10.1172/JCI66407
Journal or Publication Title: J. Clin. Invest.
Volume: 124
Number: 4
Page Range: S. 1552 - 1568
Date: 2014
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Place of Publication: ANN ARBOR
ISSN: 1558-8238
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
AMYLOID-BETA; PURKINJE-CELLS; ATAXIA; MITOCHONDRIA; DYSFUNCTION; DEPOSITION; MECHANISM; MITOPHAGY; AUTOPHAGY; ONSETMultiple languages
Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/44256

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item