Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: Genetic and bioinformatic assessment

Żekanowski, Cezary; Golan, Maciej P.; Krzyśko, Krystiana A.; Lipczyńska-Łojkowska, Wanda; Filipek, Sławomir; Kowalska, Anna; G, Rossa; Pepłońska, Beata; Styczyńska, Maria; Maruszak, Aleksandra; Religa, Dorota; Wender, M; Kulczycki, J; Barcikowska, Maria; Kuźnicki, Jacek

doi:10.1016/j.expneurol.2006.01.022

Cited by 58 publications

(55 citation statements)

References 43 publications

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“…However, due to the lack of a confirmative neuropathological diagnosis, the pathophysiological implications of this finding remain to be elucidated in further investigations. Nevertheless, there is evidence of three distinct presenilin 1 mutations causing a clinical phenotype of FTD [21,22], indicating a role of Aβ peptide metabolism in the neurodegenerative process of FTD. Interestingly, presenilin mutations are also the most common cause of familial AD.…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal Fluid Tau, p-Tau 181 and Amyloid-β<sub>38/40/42</sub> in Frontotemporal Dementias and Primary Progressive Aphasias

Bibl

Mollenhauer

Lewczuk

et al. 2010

Dement Geriatr Cogn Disord

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Background/Aims: We determined cerebrospinal fluid (CSF) concentrations of amyloid-β (Aβ)_1–38, Aβ_1–40, Aβ_1–42, total tau and phospho-tau (p-tau) in order to study their differential expression in frontotemporal dementia (FTD, n = 25) and primary progressive aphasia (PPA, n = 12) as compared to Alzheimer’s dementia (AD, n = 25) and nondemented controls (n = 20). Methods: Commercially available ELISA and electrochemiluminescence methods were applied. Results: High CSF p-tau and low ratios of Aβ_1–42/Aβ_1–40 and Aβ_1–42/Aβ_1–38, respectively, were specific for AD. CSF Aβ_1–38 was reduced in FTD as compared to each of the other diagnostic groups, including PPA. CSF tau and p-tau levels were elevated in PPA as compared to FTD. Conclusion: This is the first detailed report on biomarker patterns in PPA, indicating distinct CSF biomarker patterns in FTD and PPA as major subgroups of frontotemporal lobar degeneration. The diagnostic and pathophysiological implications of our results warrant further studies on larger and neuropathologically diagnosed patient populations.

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Section: Discussionmentioning

confidence: 99%

Cerebrospinal Fluid Tau, p-Tau 181 and Amyloid-β<sub>38/40/42</sub> in Frontotemporal Dementias and Primary Progressive Aphasias

Bibl

Mollenhauer

Lewczuk

et al. 2010

Dement Geriatr Cogn Disord

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“…Further studies are needed to determine the pathogenic status of L113P (20) and G183V (19) FTD-associated mutations in PS1. Additional investigation is also necessary to analyze functional effects of 2 more recently described FTDassociated PS1 mutations, L226F and L424H (32).…”

Section: Discussionmentioning

confidence: 99%

Familial Alzheimer disease–linked mutations specifically disrupt Ca2+ leak function of presenilin 1

et al. 2007

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Mutations in presenilins are responsible for approximately 40% of all early-onset familial Alzheimer disease (FAD) cases in which a genetic cause has been identified. In addition, a number of mutations in presenilin-1 (PS1) have been suggested to be associated with the occurrence of frontal temporal dementia (FTD). Presenilins are highly conserved transmembrane proteins that support cleavage of the amyloid precursor protein by γ-secretase. Recently, we discovered that presenilins also function as passive ER Ca 2+ leak channels. Here we used planar lipid bilayer reconstitution assays and Ca 2+ imaging experiments with presenilin-null mouse embryonic fibroblasts to analyze ER Ca 2+ leak function of 6 FAD-linked PS1 mutants and 3 known FTD-associated PS1 mutants. We discovered that L166P, A246E, E273A, G384A, and P436Q FAD mutations in PS1 abolished ER Ca 2+ leak function of PS1. In contrast, A79V FAD mutation or FTD-associated mutations (L113P, G183V, and Rins352) did not appear to affect ER Ca 2+ leak function of PS1 in our experiments. We validated our findings in Ca 2+ imaging experiments with primary fibroblasts obtained from an FAD patient possessing mutant PS1-A246E. Our results indicate that many FAD mutations in presenilins are loss-of-function mutations affecting ER Ca 2+ leak activity. In contrast, none of the FTD-associated mutations affected ER Ca 2+ leak function of PS1, indicating that the observed effects are disease specific. Our observations are consistent with the potential role of disturbed Ca 2+ homeostasis in Alzheimer disease pathogenesis. IntroductionAlzheimer disease (AD) is the most common form of age-related dementia in human beings over the age of 60 years. AD affects about 2% of populations in industrialized countries. The understanding of the molecular processes that lead to the pathogenesis of AD is immensely important in combatting this neurological disease. Most cases of AD are idiopathic and are characterized by late onset (in individuals over 60 years of age). A small fraction of AD cases (familial AD [FAD]) are characterized by an earlier onset and genetic inheritance. Mutations in presenilin-1 (PS1) and PS2 account for about 40% of all known FAD cases in which a genetic cause has been identified (1). Three missense mutations in PS1 have been suggested to be associated with frontal temporal dementia (FTD) (2), a neurological disorder that affects the frontal and temporal lobes of the brain. Presenilins are 50-kD proteins that contain 9 transmembrane domains (3, 4) and reside in the ER membrane (5). The complex of presenilins, that includes aph-1 and pen-2 subunits, is transported to the cell surface and endosomal structures, where it functions as γ-secretase. The γ-secretase cleaves the amyloid precursor protein (APP) and releases the amyloid β-peptide, the principal constituent of the amyloid plaques in the brains of AD patients. Consistent with the role of presenilins as catalytic subunits of γ-secretase (6, 7), FAD mutations in presenilins affect APP processing.

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“…Because CA1 neurons in 3×TgAD mice exhibit accumulation of Aβ oligomers and hyperphosphorylated tau, whereas CA1 neurons in PS1KI mice do not (Guo et al, 1999;Oddo et al, 2003Billings et al, 2005), our findings suggest that the adverse effects of PS1 mutations on cholinergic and NMDA-mediated synaptic plasticity are independent of Aβ and tau pathologies. Indeed, families have recently been identified in which PS1 mutations cause frontotemporal dementia [48] (Zekanowski et al, 2006) or cardiomyopathy and heart failure (Li et al, 2006), disorders that lack amyloid pathology. The mechanisms identified in the present study may explain the increased Ca 2+ responses and increased afterhyperpolarization of hippocampal neurons (Barrow et al, 2000) and the defective associative learning (Wang et al, 2004a) previously documented in studies of presenilin mutant mice.…”

Section: Discussionmentioning

confidence: 99%

Presenilin-1 mutation impairs cholinergic modulation of synaptic plasticity and suppresses NMDA currents in hippocampus slices

Wang

Greig

et al. 2009

Neurobiology of Aging

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Presenilin-1 (PS1) mutations cause many cases of early-onset inherited Alzheimer's disease, in part, by increasing the production of neurotoxic forms of amyloid β-peptide (A β). However, Aβ -independent effects of mutant PS1 on neuronal Ca 2+ homeostasis and sensitivity to excitatory neurotransmitters have been reported. Here we show that cholinergic modulation of hippocampal synaptic plasticity is impaired in PS1 mutant knockin (PS1KI) mice. Whereas activation of muscarinic receptors enhances LTP at CA1 synapses of normal mice, it impairs LTP in PS1KI mice. Similarly, mutant PS1 impairs the ability of the cholinesterase inhibitor phenserine to enhance LTP. The NMDA current is decreased in CA1 neurons of PS1KI mice and is restored by intracellular Ca 2+ chelation. Similar alterations in acetylcholine and NMDA receptor-mediated components of synaptic plasticity are evident in 3×TgAD mice with PS1, amyloid precursor protein and tau mutations, suggesting that the adverse effects of mutant PS1 on synaptic plasticity can occur in the absence or presence of amyloid and tau pathologies.

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Two novel presenilin 1 gene mutations connected with frontotemporal dementia-like clinical phenotype: Genetic and bioinformatic assessment

Cited by 58 publications

References 43 publications

Cerebrospinal Fluid Tau, p-Tau 181 and Amyloid-β<sub>38/40/42</sub> in Frontotemporal Dementias and Primary Progressive Aphasias

Cerebrospinal Fluid Tau, p-Tau 181 and Amyloid-β<sub>38/40/42</sub> in Frontotemporal Dementias and Primary Progressive Aphasias

Familial Alzheimer disease–linked mutations specifically disrupt Ca2+ leak function of presenilin 1

Presenilin-1 mutation impairs cholinergic modulation of synaptic plasticity and suppresses NMDA currents in hippocampus slices

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