RESUMEN

BACKGROUND: Hereditary inclusion body myopathy (IBMPFD) with Paget disease of bone (PDB) and frontotemporal dementia (FTD) is a rare multisystem disorder with autosomal dominant inheritance. Recently, missense mutations in the gene encoding valosin-containing protein (VCP) have been found in individuals with IBMPFD. VCP/P97, which exerts a variety of cellular functions, plays a key role in the ubiquitin-proteasome dependent degradation of cytosolic proteins and in the retrotranslocation of misfolded proteins from the endoplasmic reticulum into the cytoplasm. METHODS: The authors describe the clinical features of two kindreds in which VCP R93C and R155C missense mutations segregate and perform a histopathologic examination of brain, muscle, bone, and liver of three subjects harboring the R155C mutation. RESULTS: Frontotemporal dementia was present in 100% of affected subjects in Family F1 and 70% in Family F2, as compared with an average of 30% in previously described IBMPFD families. In contrast, PDB was a more inconstant clinical feature. Biochemical and histopathologic data are consistent with the hypothesis that VCP R155C mutation disrupts normal VCP function, leading to diffuse accumulation of ubiquitinated proteins within the cells. CONCLUSIONS: VCP mutations are present in two families in which FTD is the most prominent symptom. The histopathologic study performed in patients harboring the R155C mutation supports the hypothesis that this mutation disrupts normal VCP function, leading to diffuse accumulation of ubiquitinated proteins within the cells. IBMPFD belongs to a class of genetic diseases associated with an alteration of the ubiquitin-proteasome system.

Asunto(s)

Proteínas de Ciclo Celular/genética , Trastornos de los Cromosomas/genética , Demencia/genética , Insuficiencia Multiorgánica/genética , Miositis por Cuerpos de Inclusión/genética , Osteítis Deformante/genética , Medición de Riesgo/métodos , Adenosina Trifosfatasas , Trastornos de los Cromosomas/epidemiología , Análisis Mutacional de ADN , Demencia/epidemiología , Femenino , Francia/epidemiología , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Heterocigoto , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/epidemiología , Mutación , Miositis por Cuerpos de Inclusión/epidemiología , Osteítis Deformante/epidemiología , Linaje , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , Síndrome , Proteína que Contiene Valosina

RESUMEN

Presenilins 1 and 2 are two homologous proteins which, when mutated, appear responsible for most of the early-onset familial forms of Alzheimer's disease. Among various functional aspects, presenilins appear to behave as chaperoning partners of a series of proteins including the beta-amyloid precursor protein. Recently, presenilins were shown to interact with Rab11, a GTPase involved in intracellular transport. This suggested that Rab11-presenilin interaction could influence the routing of betaAPP and thereby modulate its maturation. In this context, we examined whether overexpression of Rab11 or its constitutively active mutant Rab11Q70L could affect betaAPP maturation in human HEK293 cells. We show here that the overexpression of both Rab11-related proteins does not modify the recovery of secreted sAPPalpha or Abeta in HEK293 cells expressing wild-type betaAPP or betaAPP harboring the Swedish double mutation. These data indicate that Rab11 does not influence betaAPP processing in HEK293 cells. However, it does not preclude the possibility for Rab11 to modulate other presenilin-mediated functions in human cells.

Asunto(s)

Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Mutación/genética , Proteínas de Unión al GTP rab/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Sustitución de Aminoácidos , Péptidos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Línea Celular , Expresión Génica , Humanos , Proteínas de la Membrana/metabolismo , Presenilina-1 , Presenilina-2 , Unión Proteica , Procesamiento Proteico-Postraduccional , Transfección , Proteínas de Unión al GTP rab/genética

RESUMEN

Determination of the effects of presenilin 1 (PSEN1) mutations, involved in autosomal dominant early-onset Alzheimer's disease (ADEOAD), on the interaction between PSEN1 and binding proteins is essential to determine which interactions are involved in Alzheimer's disease (AD) pathogenesis. The PSEN1 binding protein glycogen synthase kinase-3 beta (GSK-3 beta) has been considered as a key protein in AD pathogenesis since GSK-3 beta phosphorylates tau and hyperphosphorylated tau is a main component of neurofibrillary tangles associated to AD. We show here, using surface plasmonic resonance, that the pathogenic L392V mutation, identified in a large French ADEOAD pedigree including 39 affected members, leads to a decreased affinity to GSK-3 beta. We conclude therefore that the increase of affinity of PSEN1 to GSK-3 beta reported in previous studies is not a common effect of pathogenic mutations associated to ADEOAD.

Asunto(s)

Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/genética , Sustitución de Aminoácidos/genética , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Mutación/genética , Enfermedad de Alzheimer/enzimología , Enfermedad de Alzheimer/metabolismo , Glucógeno Sintasa Quinasa 3 , Glucógeno Sintasa Quinasas , Humanos , Leucina/genética , Presenilina-1 , Unión Proteica/genética , Proteínas Recombinantes/metabolismo , Resonancia por Plasmón de Superficie , Valina/genética

RESUMEN

Autosomal dominant early-onset Alzheimer's disease results mainly from mutations of the presenilin 1 (PSEN1) gene, which codes for an integral membrane protein of 467 amino acids. The hydrophilic loop (amino acids 263-407) of PSEN1, in which many pathogenic mutations have been localized, appears to be crucial for the protein function since it includes the binding domains to different PSEN1 partners. Using circular dichroism (CD) we analyzed the structural effects of the pathogenic L392V mutation and compared them with those of the E318G substitution. This study revealed that, the L392V mutation, in a phospholipidic medium which mimics the in vivo membrane environment, reduces the alpha helix content of the PSEN1 loop, whereas the E318G substitution, considered as a polymorphism, does not. These results suggest that the pathogenic effect of some PSEN1 mutations within the hydrophilic loop could be the alteration of the interaction to the different binding proteins through a disruption of the secondary structure.

Asunto(s)

Enfermedad de Alzheimer/genética , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Mutación/genética , Precursor de Proteína beta-Amiloide/biosíntesis , Precursor de Proteína beta-Amiloide/genética , Dicroismo Circular , Escherichia coli/metabolismo , Humanos , Linaje , Plásmidos , Presenilina-1 , Estructura Secundaria de Proteína , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química

RESUMEN

To determine the prevalence of early-onset Alzheimer disease (EOAD) and of autosomal dominant forms of EOAD (ADEOAD), we performed a population-based study in the city of Rouen (426,710 residents). EOAD was defined as onset of disease at age <61 years, and ADEOAD was defined as the occurrence of at least three EOAD cases in three generations. Using these stringent criteria, we calculated that the EOAD and ADEOAD prevalences per 100,000 persons at risk were 41.2 and 5.3, respectively. We then performed a mutational analysis of the genes for amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) in 34 families with ADEOAD ascertained in France. In 19 (56%) of these families, we identified 16 distinct PSEN1 missense mutations, including 4 (Thr147Ile, Trp165Cys, Leu173Trp, and Ser390Ile) not reported elsewhere. APP mutations, including a novel mutation located at codon 715, were identified in 5 (15%) of the families. In the 10 remaining ADEOAD families and in 9 additional autosomal dominant Alzheimer disease families that did not fulfill the strict criteria for ADEOAD, no PSEN1, PSEN2, or APP mutation was identified. These results show that (1) PSEN1 and APP mutations account for 71% of ADEOAD families and (2) nonpenetrance at age <61 years is probably infrequent for PSEN1 or APP mutations.

Asunto(s)

Edad de Inicio , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Genes Dominantes , Heterogeneidad Genética , Mutación/genética , Adulto , Anciano , Enfermedad de Alzheimer/diagnóstico , Sustitución de Aminoácidos , Precursor de Proteína beta-Amiloide/genética , Codón/genética , Análisis Mutacional de ADN , Exones/genética , Femenino , Francia/epidemiología , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Linaje , Penetrancia , Presenilina-1 , Presenilina-2 , Prevalencia

RESUMEN

Presenilin 1 (PS1) mutations account for the majority of early-onset dominant cases of familial Alzheimer's disease. Presenilins (PSs) are located in many intra-cellular compartments such as the endoplasmic reticulum, Golgi apparatus, nuclear region and vesicular structures. These proteins include from seven to nine putative transmembrane domains, with the N- and C-terminal ends and a large hydrophilic loop orientated towards the cytoplasm. We report an interaction between the human PS1 or PS2 hydrophilic loop and Rab11, a small GTPase belonging to the Ras-related superfamily. Interaction domains were mapped to codons 374-400 for PS1 and to codons 106-179 for Rab11, a region including the fourth GTP-binding domain. Considering the implication of Rab proteins in vesicular transport pathways, the PS-Rab11 inter-action suggests that PSs might be involved in amyloid precursor protein vesicular routing.

Asunto(s)

GTP Fosfohidrolasas/metabolismo , Proteínas de Unión al GTP/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Unión al GTP rab , Secuencia de Aminoácidos , Animales , Sitios de Unión , Transporte Biológico/fisiología , Células COS , Humanos , Datos de Secuencia Molecular , Presenilina-1 , Conformación Proteica , Saccharomyces cerevisiae/metabolismo

RESUMEN

We have identified a novel beta amyloid precursor protein (betaAPP) mutation (V715M-betaAPP770) that cosegregates with early-onset Alzheimer's disease (AD) in a pedigree. Unlike other familial AD-linked betaAPP mutations reported to date, overexpression of V715M-betaAPP in human HEK293 cells and murine neurons reduces total Abeta production and increases the recovery of the physiologically secreted product, APPalpha. V715M-betaAPP significantly reduces Abeta40 secretion without affecting Abeta42 production in HEK293 cells. However, a marked increase in N-terminally truncated Abeta ending at position 42 (x-42Abeta) is observed, whereas its counterpart x-40Abeta is not affected. These results suggest that, in some cases, familial AD may be associated with a reduction in the overall production of Abeta but may be caused by increased production of truncated forms of Abeta ending at the 42 position.

Asunto(s)

Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/biosíntesis , Precursor de Proteína beta-Amiloide/genética , Mutación Puntual , Edad de Inicio , Sustitución de Aminoácidos , Péptidos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/biosíntesis , Línea Celular , Femenino , Humanos , Masculino , Metionina , Mutagénesis Sitio-Dirigida , Linaje , Fenotipo , Proteínas Recombinantes/biosíntesis , Transfección , Valina

RESUMEN

This review reports epidemiological data and biological mechanisms about the Apolipoprotein E gene allele epsilon 4 that is a major risk factor for Alzheimer's disease (AD). The second part describes the three genes, amyloid precusor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2) genes, which when mutated cause early-onset autosomal dominant AD. Mutations on each of these genes have as a common consequence elevated levels of A beta (42,3).

Asunto(s)

Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/psicología , Apolipoproteína E4 , Apolipoproteínas E/metabolismo , Marcadores Genéticos , Humanos , Factores de Riesgo

RESUMEN

Frontotemporal dementia and parkinsonism (FTDP) is the second most common cause of neurodegenerative dementia after Alzheimer's disease. Recently, several kindreds with an autosomal dominant form of FTDP have been reported and in some families the pathological locus was mapped to a 2 cM interval on 17q21-22. The MAPT gene, located on 17q21 and coding for the human microtubule-associated protein tau, is a strong candidate gene, since tau-positive neuronal inclusions have been observed in brains from some FTDP patients. Direct sequencing of the MAPT exonic sequences in 21 French FTDP families revealed in six index cases the same missense mutation in exon 10 resulting in a Pro-->Leu change at amino acid 301. Co-segregation of this mutation with the disease was demonstrated by restriction fragment analysis in two families for which several affected relatives were available. The Pro301Leu mutation was not observed in either 50 unrelated French controls or in 11 patients with sporadic frontotemporal dementia. This mutation, which occurs in the second microtubule-binding domain of the MAPT protein, is likely to have a drastic functional consequence. The observation of this mutation in several FTDP families might suggest that disruption of binding of MAPT protein to the microtubule is a key event in the pathogenesis of FTDP.

Asunto(s)

Demencia/genética , Mutación Missense , Enfermedad de Parkinson/genética , Proteínas tau/genética , Adulto , Edad de Inicio , Anciano , Demencia/patología , Femenino , Lóbulo Frontal/patología , Humanos , Masculino , Persona de Mediana Edad , Linaje , Lóbulo Temporal/patología

RESUMEN

The presenilin 1 (PS1) gene, located on chromosome 14, is the major gene involved in the autosomal dominant forms of early onset Alzheimer's disease (AD). In order to estimate the frequency of de novo PS1 mutations, we have sequenced the PS1 open reading frame in 13 clinically diagnosed patients with no affected relatives, who had developed AD before the age of 50. In one case with onset at 37 years, we identified a missense mutation resulting in a methionine to lysine substitution at codon 139 of the PS1 gene. This substitution is the fourth identified at the same codon. This study, in agreement with previous reports, suggests that de novo PS1 mutations can occur but at a low frequency.

Asunto(s)

Enfermedad de Alzheimer/genética , Proteínas de la Membrana/genética , Mutación , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linaje , Presenilina-1

RESUMEN

We have identified a novel Alzheimer's disease family in which affected subjects had a very young age of onset (range 29-35 years). Neuropathological confirmation of the diagnosis was obtained for one patient. Molecular analysis shows that within this family the disease results from a missense mutation at codon 235 of the presenilin 1 (PS-1) gene. Two patients had exhibited generalized tonico-clonic seizures several years before the onset of dementia. Whether this particular clinical feature is a consequence of the PS-1 mutation remains to be established. The Leu235Pro mutation is, to our knowledge, the PS-1 mutation associated with the youngest age of AD onset, which suggests that it has a drastic effect on PS-1 function.

Asunto(s)

Enfermedad de Alzheimer/genética , Proteínas de la Membrana/genética , Mutación/genética , Adulto , Edad de Inicio , Humanos , Presenilina-1