title: Familial frontotemporal dementia-associated presenilin-1 c.548G>T mutation causes decreased mRNA expression and reduced presenilin function in knock-in mice.
abstract: Mutations in the presenilin-1 (PSEN1) gene are associated with familial Alzheimer's disease and frontotemporal dementia (FTD). Interestingly, neuropathological analysis of a Belgian FTD family carrying a PSEN1 c.548G>T mutation confirmed neurodegeneration in the absence of amyloid plaques. To investigate the impact of the c.548G>T mutation on presenilin-1 (PS1) function in vivo, we introduced this mutation into the genomic Psen1 locus. The resulting c.548G>T knock-in (KI) mice are viable but express markedly lower levels of Psen1 mRNA and protein in the brain. This reduction is due to production of aberrantly spliced transcripts lacking either exon 6 or exons 6 and 7 and their subsequent degradation via non-sense-mediated decay (NMD); inhibition of NMD by cycloheximide treatment stabilized these transcripts and restored the level of Psen1 mRNA in KI/KI brains. Interestingly, the reduction of Psen1 mRNA expression and the degradation of aberrant Psen1 splice products occur exclusively in the brain but not in other tissues. Consistent with decreased Psen1 expression, γ-secretase activity was strongly reduced in the cerebral cortex of KI mice, as measured by de novo γ-secretase-mediated cleavage of APP and Notch. Moreover, PS1 expressed from Psen1 cDNA carrying the c.548G>T mutation displayed normal γ-secretase activity in cultured cells, indicating that the corresponding p.183G>V amino acid substitution does not affect γ-secretase activity. Finally, Psen1 c.548G>T(KI/KI);Psen2(-/-) mice exhibited mild spatial memory deficits in the Morris water maze task. Together, our findings demonstrate that the c.548G>T mutation results in a brain-specific loss of presenilin function due to decreased Psen1 mRNA expression.
authors.affiliation: Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Watanabe
authors.forename: Dan
authors.initials: D
authors.lastname: Xia
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kanekiyo
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Kelleher
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
mesh_terms: D000483:Alleles; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D003513:Cycloheximide / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics / Q000523:psychology; D051379:Mice; D009154:Mutation / Q000502:physiology*; D053764:Presenilin-1 / Q000235:genetics*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D053764:Presenilin-1; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D016875:tau Proteins; D003513:Cycloheximide; D053829:Amyloid Precursor Protein Secretases