Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis
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Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis. / Sepulveda-Falla, Diego; Barrera-Ocampo, Alvaro A; Hagel, Christian; Korwitz, Anne; Vinueza-Veloz, Maria Fernanda; Zhou, Kuikui; Schonewille, Martijn; Zhou, Haibo; Velazquez-Perez, Luis; Rodriguez-Labrada, Roberto; Villegas, Andres; Ferrer, Isidro; Lopera, Francisco; Langer, Thomas; De Zeeuw, Chris I; Glatzel, Markus.
in: J CLIN INVEST, Jahrgang 124, Nr. 4, 01.04.2014, S. 1552-67.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis
AU - Sepulveda-Falla, Diego
AU - Barrera-Ocampo, Alvaro A
AU - Hagel, Christian
AU - Korwitz, Anne
AU - Vinueza-Veloz, Maria Fernanda
AU - Zhou, Kuikui
AU - Schonewille, Martijn
AU - Zhou, Haibo
AU - Velazquez-Perez, Luis
AU - Rodriguez-Labrada, Roberto
AU - Villegas, Andres
AU - Ferrer, Isidro
AU - Lopera, Francisco
AU - Langer, Thomas
AU - De Zeeuw, Chris I
AU - Glatzel, Markus
PY - 2014/4/1
Y1 - 2014/4/1
N2 - 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.
AB - 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.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Alzheimer Disease
KW - Amino Acid Substitution
KW - Amyloid beta-Protein Precursor
KW - Animals
KW - Calcium
KW - Case-Control Studies
KW - Cell Line
KW - Cerebellum
KW - Disease Models, Animal
KW - Endoplasmic Reticulum
KW - Female
KW - Genes, Dominant
KW - Heterozygote
KW - Homeostasis
KW - Humans
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Mutant Strains
KW - Mice, Transgenic
KW - Middle Aged
KW - Mitochondria
KW - Models, Neurological
KW - Mutation, Missense
KW - Presenilin-1
KW - Purkinje Cells
U2 - 10.1172/JCI66407
DO - 10.1172/JCI66407
M3 - SCORING: Journal article
C2 - 24569455
VL - 124
SP - 1552
EP - 1567
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 4
ER -