TY - JOUR T1 - Familial Frontotemporal Dementia-Associated <em>Presenilin-1 c.548G&gt;T</em> Mutation Causes Decreased mRNA Expression and Reduced Presenilin Function in Knock-In Mice JF - The Journal of Neuroscience JO - J. Neurosci. SP - 5085 LP - 5096 DO - 10.1523/JNEUROSCI.0317-12.2012 VL - 32 IS - 15 AU - Hirotaka Watanabe AU - Dan Xia AU - Takahisa Kanekiyo AU - Raymond J. Kelleher III AU - Jie Shen Y1 - 2012/04/11 UR - http://www.jneurosci.org/content/32/15/5085.abstract N2 - 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&gt;T mutation confirmed neurodegeneration in the absence of amyloid plaques. To investigate the impact of the c.548G&gt;T mutation on presenilin-1 (PS1) function in vivo, we introduced this mutation into the genomic Psen1 locus. The resulting c.548G&gt;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&gt;T mutation displayed normal γ-secretase activity in cultured cells, indicating that the corresponding p.183G&gt;V amino acid substitution does not affect γ-secretase activity. Finally, Psen1 c.548G&gt;TKI/KI;Psen2−/− mice exhibited mild spatial memory deficits in the Morris water maze task. Together, our findings demonstrate that the c.548G&gt;T mutation results in a brain-specific loss of presenilin function due to decreased Psen1 mRNA expression. ER -