title: Familial Alzheimer's disease-associated presenilin-1 alters cerebellar activity and calcium homeostasis.
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.
authors.forename: Diego
authors.initials: D
authors.lastname: Sepulveda-Falla
authors.forename: Alvaro
authors.initials: A
authors.lastname: Barrera-Ocampo
authors.forename: Christian
authors.initials: C
authors.lastname: Hagel
authors.forename: Anne
authors.initials: A
authors.lastname: Korwitz
authors.forename: Maria Fernanda
authors.initials: MF
authors.lastname: Vinueza-Veloz
authors.forename: Kuikui
authors.initials: K
authors.lastname: Zhou
authors.forename: Martijn
authors.initials: M
authors.lastname: Schonewille
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhou
authors.forename: Luis
authors.initials: L
authors.lastname: Velazquez-Perez
authors.forename: Roberto
authors.initials: R
authors.lastname: Rodriguez-Labrada
authors.forename: Andres
authors.initials: A
authors.lastname: Villegas
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
authors.forename: Francisco
authors.initials: F
authors.lastname: Lopera
authors.forename: Thomas
authors.initials: T
authors.lastname: Langer
authors.forename: Chris I
authors.initials: CI
authors.lastname: De Zeeuw
authors.forename: Markus
authors.initials: M
authors.lastname: Glatzel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D019943:Amino Acid Substitution; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016022:Case-Control Studies; D002460:Cell Line; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000473:pathology; D005260:Female; D005799:Genes, Dominant; D006579:Heterozygote; D006706:Homeostasis; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D008959:Models, Neurological; D020125:Mutation, Missense; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism*; D011689:Purkinje Cells / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1; C580804:presenilin 1, mouse; D002118:Calcium