A novel presenilin 1 mutation associated with Pick's disease but not β‐amyloid plaques

Dermaut, Bart; Kumar‐Singh, Samir; Engelborghs, S.; Theuns, Jessie; Rademakers, Rosa; Saerens, J.; Pickut, Barbara A.; Peeters, Karin; Broeck, Marleen Van den; Vennekens, Kristel M.; Claes, S.; Cruts, Marc; Cras, Patrick; Martin, J. J.; Broeckhoven, Christine Van; Deyn, Peter Paul De

doi:10.1002/ana.20083

Cited by 201 publications

(140 citation statements)

References 42 publications

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“…The diagnosis of FTD was based on the Lund and Manchester criteria as described [The Lund and Manchester Groups, 1994;Le Ber et al, 2007]. Previous mutation analyses identified a MAPT mutation in three Belgian and six French FTD patients, and a presenilin 1 (PSEN1) [MIM# 104311] mutation in one Belgian patient [van der Zee et al, 2006;Dermaut et al, 2004;Le Ber et al, 2007]. In addition to patients, 459 unrelated neurologically healthy Belgian and 187 French control individuals were analyzed for PGRN variations.…”

Section: Subjectsmentioning

confidence: 99%

Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia

et al. 2007

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Null mutations in the progranulin gene (GRN, PGRN) were recently identified as the causal mechanism underlying frontotemporal dementia (FTD) with ubiquitin-positive brain pathology linked to chromosome 17 (FTDU-17). In a Belgian and French FTD series comprising 332 patients, we reported 13 PGRN null mutations which were mainly nonsense and frameshift mutations resulting in premature stop codons. Here we report in the same patient series three missense mutations of which two (c.743C>T, p.Pro248Leu and c.1294C>T, p.Arg432Cys) were predicted in silico to severely affect protein folding and/or processing leading to PGRN protein haploinsufficiency. In addition, we observed three sequence variations in the 5' regulatory region that might potentially affect PGRN transcription activity. Our findings extend the mutation spectrum in PGRN leading to loss of functional PGRN as the basis for FTD.

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Section: Subjectsmentioning

confidence: 99%

Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia

et al. 2007

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“…A serious challenge to that model has arisen with the discovery of a family of individuals with a PS mutation manifesting clinically as frontotemporal dementia (FTD) and pathologically as "pure" NFT disease, i.e., there is no parenchymal or cerebrovascular amyloidosis in FTD (29). FTD is usually due to mutations involving the cytoskeletal protein tau, and these diseases are therefore called tauopathies (30).…”

Section: What Is the Role Of Aβ In Common Forms Of Ad?mentioning

confidence: 99%

“…No pathogenic PS1 mutation has heretofore been described as associating with pure NFT pathology. Furthermore, no generation of excess levels of Aβ42 was observed when the FTD mutant PS was transfected into cultured cells (29). The possibility remains that the PS1 mutation is acting by elevating the levels of toxic Aβ oligomers that induce tangle formation but not plaques, but no precedent exists for such a pathomechanism.…”

Section: What Is the Role Of Aβ In Common Forms Of Ad?mentioning

confidence: 99%

The role of cerebral amyloid accumulation in common forms of Alzheimer disease

Gandy¹

2005

Journal of Clinical Investigation

139

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For approximately 80 years following Alzheimer's description of the disease that bears his name, a gulf divided researchers who believed that extracellular deposits of the amyloid β (Aβ) peptide were pathogenic from those who believed that the deposits were secondary detritus. Since 1990, the discoveries of missense mutations in the Aβ peptide precursor (APP) and the APP-cleaving enzyme presenilin 1 (PS1) have enabled much progress in understanding the molecular, cellular, and tissue pathology of the aggregates that accumulate in the interstices of the brains of patients with autosomal dominant familial Alzheimer disease (AD). Clarification of the molecular basis of common forms of AD has been more elusive. The central questions in common AD focus on whether cerebral and cerebrovascular Aβ accumulation is (a) a final neurotoxic pathway, common to all forms of AD; (b) a toxic by-product of an independent primary metabolic lesion that, by itself, is also neurotoxic; or (c) an inert by-product of an independent primary neurotoxic reaction. Antiamyloid medications are entering clinical trials so that researchers can evaluate whether abolition of cerebral amyloidosis can mitigate, treat, or prevent the dementia associated with common forms of AD. Successful development of antiamyloid medications is critical for elucidating the role of Aβ in common AD.

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“…These A␤42-independent cellular changes may also contribute to the onset and/or neuropathological characteristics of presenilindependent FAD (22). Interestingly, certain pathogenic mutations in PS1 cause frontotemporal dementia with profound neurofibrillary tangle pathology in the absence of amyloid plaques (23). However, it is currently unknown how the presenilins mediate multiple cellular processes in addition to their role as a protease subunit.…”

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confidence: 99%

Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism

Landman

Jeong

Shin

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

126

121

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Phosphatidylinositol 4,5-bisphosphate (PIP2) is an important cellular effector whose functions include the regulation of ion channels and membrane trafficking. Aberrant PIP 2 metabolism has also been implicated in a variety of human disease states, e.g., cancer and diabetes. Here we report that familial Alzheimer's disease (FAD)-associated presenilin mutations cause an imbalance in PIP 2 metabolism. We find that the transient receptor potential melastatin 7 (TRPM7)-associated Mg 2؉ -inhibited cation (MIC) channel underlies ion channel dysfunction in presenilin FAD mutant cells, and the observed channel deficits are restored by the addition of PIP 2, a known regulator of the MIC/TRPM7 channel. Lipid analyses show that PIP 2 turnover is selectively affected in FAD mutant presenilin cells. We also find that modulation of cellular PIP 2 closely correlates with 42-residue amyloid ␤-peptide (A␤42) levels. Our data suggest that PIP 2 imbalance may contribute to Alzheimer's disease pathogenesis by affecting multiple cellular pathways, such as the generation of toxic A␤42 as well as the activity of the MIC/TRPM7 channel, which has been linked to other neurodegenerative conditions. Thus, our study suggests that brain-specific modulation of PIP 2 may offer a therapeutic approach in Alzheimer's disease.␤-amyloid precursor protein ͉ channel ͉ secretase ͉ transient receptor potential melastatin 7 (TRPM7) ͉ capacitative calcium entry

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A novel presenilin 1 mutation associated with Pick's disease but not β‐amyloid plaques

Cited by 201 publications

References 42 publications

Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia

Mutations other than null mutations producing a pathogenic loss of progranulin in frontotemporal dementia

The role of cerebral amyloid accumulation in common forms of Alzheimer disease

Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism

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