Frontotemporal Dementia-like Phenotypes Associated With Presenilin-1 Mutations
Frontal behavioral changes may be the presenting features of single-photon emission tomography (presenilin-1 [PS-1]) mutations, the most common cause of familial Alzheimer's disease (AD). The authors describe a PS-1 (M233L) mutation with the features of frontotemporal dementia (FTD) and review the literature. PS-1 mutations may produce FTD-like phenotypes with the neuropathology of AD. Some PS-1 mutations have additional Pick's bodies, a neuropathological marker of FTD, and a report of a PS-1 (G183V) mutation found Pick's bodies without amyloid plaques. The patient and the literature suggest that PS-1 mutations result in an overlapping continuum of the clinical and neuropathological features of AD and FTD. In PS-1 mutations, the expression of AD or FTD may depend on the degree of loss of function of the PS-1 gene and the resultant tau pathophysiology.
Available from: Ehud Cohen
- "Interestingly, many AD-causing mutations in the sequence of PS1 do not elevate total Ab levels (Chavez-Gutierrez et al, 2012), suggesting that noncanonical mechanisms are accountable for the development of certain AD cases by attenuating PS1 function. Moreover, while most PS1 mutations cause familial AD (fAD), certain amino acid substations in the sequence of PS1 were reported to initiate FTD (Mendez & McMurtray, 2006). Similarly, mutations in the sequence of the highly aggregative prion protein (PrP) are associated with the emergence of at least three familial neurodegenerative disorders: Creutzfeldt–Jakob disease (CJD), fatal familial insomnia (FFI), and Gerstmann– Sträussler–Scheinker syndrome (GSS) (reviewed in Aguzzi & Polymenidou, 2004). "
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ABSTRACT: Do different neurodegenerative maladies emanate from the failure of a mutual protein folding mechanism? We have addressed this question by comparing mutational patterns that are linked to the manifestation of distinct neurodegenerative disorders and identified similar neurodegeneration-linked proline substitutions in the prion protein and in presenilin 1 that underlie the development of a prion disorder and of familial Alzheimer's disease (fAD), respectively. These substitutions were found to prevent the endoplasmic reticulum (ER)-resident chaperone, cyclophilin B, from assisting presenilin 1 to fold properly, leading to its aggregation, deposition in the ER, reduction of c-secretase activity, and impaired mito-chondrial distribution and function. Similarly, reduced quantities of the processed, active presenilin 1 were observed in brains of cyclophilin B knockout mice. These discoveries imply that reduced cyclophilin activity contributes to the development of distinct neurodegenerative disorders, propose a novel mechanism for the development of certain fAD cases, and support the emerging theme that this disorder can stem from aberrant presenilin 1 function. This study also points at ER chaperones as targets for the development of counter-neurodegeneration therapies.
Available from: Takahisa Kanekiyo
- "A large proportion (~20–50%) of FTD cases have a familial component, and mutations in microtubule-associated protein tau and progranulin genes are the most frequent genetic causes (Galimberti and Scarpini, 2010). Interestingly, mutations in the presenilin-1 (PSEN1) and presenilin-2 (PSEN2) genes, which are the major cause of familial AD, have also been implicated in FTD (Mendez and McMurtray, 2006). Since the first identification of the PSEN1 c.338T>C mutation in cases of familial dementia with prominent clinical frontotemporal features (Raux et al., 2000), more than 10 mutations in the PSEN genes have been associated with clinical diagnoses of FTD, in some cases accompanied by frontotemporal atrophy and frontotemporal hypoperfusion on neuroimaging studies (Rippon et al., 2003; Dermaut et al., 2004; Halliday et al., 2005; Zekanowski et al., 2006; Bernardi et al., 2009; de Bot et al., 2009; Marcon et al., 2009; Gallo et al., 2010; Borroni et al., 2011). "
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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.
Available from: Vincent Deramecourt
- "D'autres mutations, moins fréquentes se situent sur le chromosome 3, gène de CHMP2B (Chromatin Modifying Protein 2B , sur le chromosome 9, gène de VCP (valosin-containing protein) responsable aussi d'une myopathie à inclusions et d'une maladie de Paget osseuse , sur le chromosome 1, gène de TARDBP (transactive response (TAR)-DNA-binding protein) à l'origine de la protéine TDP-43   voire sur le chromosome 16, gène de FUS (Fused in sarcoma) plutôt impliqué dans la SLA . À noter que des phénotypes de DFT ont été décrits dans le cas de mutations PS1 (chromosome 14) à l'origine de maladie d'Alzheimer . "
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ABSTRACT: Frontotemporal dementias (FTD) are defined by a gradual change in social conduct, behavior and language, associated with frontal and anterior temporal lobe degeneration. The clinicalfeatures depend on the location of the degenerative process. In the last 20 years, increasingly specific and sensitive operational criteria have been established. Ongoing neuropathological and genetic studies have highlighted overlaps between FTD, motor neuron disease, and atypical parkinsonian syndromes (supranuclear palsy, corticobasal degeneration). They have also provided a better knowledge of the pathophysiology of FTD, and new specific therapeutic targets. These dementias, which usually occur before the age of 65 years, are now better recognized but are still underdiagnosed and often initially mistaken for psychiatric illnesses. Healthcare professionals managing these patients must therefore be better informed Serotonergic agents provide a symptomatic improvement, but environmental adaptation, prevention of language and swallowing difficulties, and information and support for the family and caregivers remain essential.
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