Spastic paraparesis and atypical dementia caused by PSEN1 mutation (P264L), responsible for Alzheimer's disease

Jacquemont, M-L

doi:10.1136/jmg.39.2.e2

Cited by 21 publications

(19 citation statements)

References 11 publications

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“…We searched for such a correlation and discovered that the majority of “functional” PS1-FAD mutants have been linked with the CWP/SP phenotype in AD patients. These mutations are PS1-ΔE9 (CWP/SP) [28, 29], P264L (CWP/SP) [30] and C410Y (CWP, Parkinsonism) [31] (Table 1). …”

Section: Resultsmentioning

confidence: 99%

Familial Alzheimer's Disease Mutations in Presenilins: Effects on Endoplasmic Reticulum Calcium Homeostasis and Correlation with Clinical Phenotypes

Nelson

Supnet

Liu

et al. 2010

JAD

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Mutations in presenilins (PS1 and PS2) are responsible for approximately 40% of all early onset familial Alzheimer’s disease (FAD) monogenic cases. Presenilins (PSs) function as the catalytic subunit of γ-secretase and support cleavage of the amyloid precursor protein (APP). We previously discovered that PSs also function as passive endoplasmic reticulum (ER) calcium (Ca2+) leak channels and that most FAD mutations in PSs affected their ER Ca2+ leak function. To further validate the relevance of our findings to human disease, we here performed Ca2+ imaging experiments with lymphoblasts established from FAD patients. We discovered that most FAD mutations in PSs disrupted ER Ca2+ leak function and resulted in increased ER Ca2+ pool in human lymphoblasts. However, we found that a subset of PS1 FAD mutants supported ER Ca2+ leak activity, as ER Ca2+ pool was unaffected in lymphoblasts. Most of the “functional” mutations for ER Ca2+ leak were clustered in the exon 8–9 area of PSEN1 gene and segregated with the cotton wool plaques and spastic paraparesis (CWP/SP) clinical phenotype occasionally observed in PS1 FAD patients. Our findings with the “functional” and “non-functional” PS1 FAD mutants were confirmed in Ca2+ rescue experiments with PS double-knockout (DKO) mouse embryonic fibroblasts. Based on the combined effects of the PS1 FAD mutations on ER Ca2+ leak and γ-secretase activities we propose a model that explains the heterogeneity observed in FAD. The proposed model has implications for understanding the pathogenesis of both familial and sporadic AD.

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Section: Resultsmentioning

confidence: 99%

Familial Alzheimer's Disease Mutations in Presenilins: Effects on Endoplasmic Reticulum Calcium Homeostasis and Correlation with Clinical Phenotypes

Nelson

Supnet

Liu

et al. 2010

JAD

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“…2B). Indeed, the only mutation located in quadrant IV (PS1-ΔE9) results in the most robust and penetrant CWP/SP clinical phenotype (Brooks et al, 2003; Jacquemont et al, 2002). …”

Section: Er Ca2+ Leak and Variant Admentioning

confidence: 99%

Presenilins function in ER calcium leak and Alzheimer's disease pathogenesis

Supnet

Bezprozvanny

2011

Cell Calcium

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Alzheimer disease (AD) is the most common neurodegenerative disorder worldwide and is at present, incurable. The accumulation of toxic amyloid-beta (Aβ) peptide aggregates in AD brain are thought to trigger the extensive synaptic loss and neurodegeneration linked to cognitive decline, an idea that underlies the amyloid hypothesis of AD etiology in both the familal (FAD) and sporadic forms of the disease. Genetic mutations causing FAD also result in the dysregulation of neuronal calcium (Ca2+) handling and may contribute to AD pathogenesis, an idea termed the calcium hypothesis of AD. Mutations in presenilin proteins account for majority of FAD cases. Presenilins function as catalytic subunit of γ-secretase involved in generation of Aβ peptide Recently, we discovered that presenilns function as low-conductance, passive ER Ca2+ leak channels, independent of γ-secretase activity. We further discovered that many FAD mutations in presenilins results in loss of ER Ca2+ leak function activity and Ca2+ overload in the ER. These results provided potential explanation for abnormal Ca2+ signaling observed in FAD cells with mutations in presenilns. The implications of these findings for understanding AD pathogenesis are discussed in this article.

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“…Jacquemont et al. (2002) reported a small French family with a PSEN1 P264L mutation wherein individuals had dementia described as not typical of AD and preceding SP.…”

Section: Alzheimer’s Disease Psen1 Mutations and Spastic Paraparesismentioning

confidence: 99%

“…There was a family history of dementia in his sister (died aged 63), mother (died aged 70) and maternal grandmother (age at death unknown). Walking difficulties were noted in his mother (Jacquemont et al. 2002).…”

Section: Alzheimer’s Disease Psen1 Mutations and Spastic Paraparesismentioning

confidence: 99%

Variable phenotype of Alzheimer’s disease with spastic paraparesis

Karlström

Brooks

Broe

et al. 2007

Journal of Neurochemistry

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Alzheimer's disease (AD) is one of the most common neurodegenerative diseases with a prevalence of 5-10% in individuals over 65 years. Approximately, 70% of all patients with dementia have AD (Hardy 1997). AD is characterized by cognitive impairment most notably memory loss, neuronal degeneration, amyloid plaques, cholinergic deficiency in many areas of gray matter, and the formation of abnormal cytoskeletal structures [neurofibrillary tangles (NFTs)]. The duration of AD varies widely between 5 and 15 years and the disease represents a large medical, social and economic problem.A small percentage of patients with AD have an autosomal dominant illness that is characterized by the onset of disease at an early age (< 65 years). Most pedigrees with familial AD (FAD) have been shown to carry mutations in one of the amyloid precursor protein (APP), presenilin 1 (PSEN1) or PSEN2 genes (Hardy 1997; Price and Sisodia 1998) with over 160 PSEN1 mutations, 10 PSEN2 mutations and 28 APP mutations identified to date (see AD mutation databases http://www.alzforum.org/res/com/mut or http://www.molgen. ua.ac.be/ADMutations). AbstractPedigrees with familial Alzheimer's disease (AD) show considerable phenotypic variability. Spastic paraparesis (SP), or progressive spasticity of the lower limbs is frequently hereditary and exists either as uncomplicated (paraparesis alone) or complicated (paraparesis and other neurological features) disease subtypes. In some AD families, with presenilin-1 (PSEN1) mutations, affected individuals also have SP. These PSEN1 AD pedigrees frequently have a distinctive and variant neuropathology, namely large, non-cored plaques without neuritic dystrophy called cotton wool plaques (CWP). The PSEN1 AD mutations giving rise to CWP produce unusually high levels of the amyloid b peptide (Ab) ending at position 42 or 43, and the main component of CWP is amino-terminally truncated forms of amyloid b peptide starting after the alternative b-secretase cleavage site at position 11. This suggests a molecular basis for the formation of CWP and an association with both SP and AD. The SP phenotype in some PSEN1 AD pedigrees also appears to be associated with a delayed onset of dementia compared with affected individuals who present with dementia only, suggesting the existence of a protective factor in some individuals with SP. Variations in neuropathology and neurological symptoms in PSEN1 AD raise the prospect that modifier genes may underlie this phenotypic heterogeneity.

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Spastic paraparesis and atypical dementia caused by PSEN1 mutation (P264L), responsible for Alzheimer's disease

Cited by 21 publications

References 11 publications

Familial Alzheimer's Disease Mutations in Presenilins: Effects on Endoplasmic Reticulum Calcium Homeostasis and Correlation with Clinical Phenotypes

Familial Alzheimer's Disease Mutations in Presenilins: Effects on Endoplasmic Reticulum Calcium Homeostasis and Correlation with Clinical Phenotypes

Presenilins function in ER calcium leak and Alzheimer's disease pathogenesis

Variable phenotype of Alzheimer’s disease with spastic paraparesis

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