RESUMO
Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10-12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10-12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10-8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.
Assuntos
Apolipoproteínas E , Demência Frontotemporal , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Proteínas tau , Humanos , Demência Frontotemporal/genética , Proteínas tau/genética , Apolipoproteínas E/genética , Masculino , Feminino , Idoso , Polimorfismo de Nucleotídeo Único , Loci Gênicos , Pessoa de Meia-Idade , Estudos de Casos e Controles , Proteínas da MielinaRESUMO
BACKGROUND: Clinical researchers increasingly embrace social media in their professional lives. The digital revolution has provided new routes for sharing data, disseminating results, and promoting the impact of scientific findings. In this study, we explored the attitude of the members of the Italian Society of Neurology for the study of dementia (SINdem) to use social media with the aim to set up possible corrective actions to maximize digitalization benefits at the individual and community levels. METHOD: An ad hoc designed survey was implemented and distributed to the SINdem and SINdem4Juniors communities. It explored the different use of social media taking into account frequency, type of social media use (active vs passive; professional vs private). Descriptive statistical analyses were performed alongside statistical comparisons to highlight possible differences in the use. RESULTS: We collected 133 answers showing a prominent use of social media in private life (t(132) = 21.1, p < 0.001), with SINdem4Juniors members showing a higher private use compared to the older SINdem colleagues. Professional use was mainly limited to passive activities such as following others' social profiles (t(132) = 11.9, p < 0.001). DISCUSSION: Overall scenario suggests that professional use of social media is very limited in both SINdem and SINdem4juniors communities. This evidence points to an urgent need for training interventions and top-down strategies aimed at improving collaboration, dissemination, and sharing through social media among individuals belonging to the same scientific-professional community.
Assuntos
Demência , Mídias Sociais , Sociedades Médicas , Humanos , Mídias Sociais/estatística & dados numéricos , Itália , Masculino , Feminino , Pessoa de Meia-Idade , Neurologia , Adulto , Idoso , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Spinocerebellar ataxia 17 (SCA17) is a rare autosomal dominant form of inherited ataxia, caused by heterozygous trinucleotide repeat expansions encoding glutamine in the TATA box-binding protein (TBP) gene. CASE DESCRIPTION: We describe the clinical history, neuropsychological, and neuroimaging findings of a 42-year-old patient who presented for medical attention showing prevalent behavioral and cognitive problems along with progressively worsening gait disturbances. The patient's family history indicated the presence of SCA17 in the maternal lineage. Genetic analysis confirmed a heterozygous 52-CAG pathological expansion repeat in TBP (normal interval, 25-40 CAG. Brain 18-fluorodeoxyglucose positron emission tomography (FDG-PET) showed bilateral hypometabolism in the sensorimotor cortex, with a slight predominance on the right, as well as in the striatal nuclei and thalamic hypermetabolism, a finding similar to what is observed in Huntington's disease. The patient also underwent neuropsychological evaluation, which revealed mild cognitive impairment and difficulties in social interaction and understanding other's emotions (Faux Pas Test and Reading the Mind in the Eyes Test). CONCLUSION: Our report emphasizes the importance of considering SCA17 as a possible diagnosis in patients with a prevalent progressive cognitive and behavioral disorders, even with a pattern of FDG-PET hypometabolism not primarily indicative of this disease.
Assuntos
Disfunção Cognitiva , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons , Ataxias Espinocerebelares , Adulto , Humanos , Encéfalo/diagnóstico por imagem , Ataxia Cerebelar/diagnóstico por imagem , Ataxia Cerebelar/genética , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/genética , Disfunção Cognitiva/etiologia , Testes Neuropsicológicos , Transtornos do Comportamento Social/diagnóstico por imagem , Transtornos do Comportamento Social/etiologia , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/genética , Proteína de Ligação a TATA-Box/genéticaRESUMO
Alzheimer's disease (AD) represents the most prevalent type of dementia in elderly people, primarily characterized by brain accumulation of beta-amyloid (Aß) peptides, derived from Amyloid Precursor Protein (APP), in the extracellular space (amyloid plaques) and intracellular deposits of the hyperphosphorylated form of the protein tau (p-tau; tangles or neurofibrillary aggregates). The Nerve growth factor receptor (NGFR/p75NTR) represents a low-affinity receptor for all known mammalians neurotrophins (i.e., proNGF, NGF, BDNF, NT-3 e NT-4/5) and it is involved in pathways that determine both survival and death of neurons. Interestingly, also Aß peptides can blind to NGFR/p75NTR making it the "ideal" candidate in mediating Aß-induced neuropathology. In addition to pathogenesis and neuropathology, several data indicated that NGFR/p75NTR could play a key role in AD also from a genetic perspective. Other studies suggested that NGFR/p75NTR could represent a good diagnostic tool, as well as a promising therapeutic target for AD. Here, we comprehensively summarize and review the current experimental evidence on this topic.
Assuntos
Doença de Alzheimer , Idoso , Animais , Humanos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Mamíferos/metabolismo , Fator de Crescimento Neural/farmacologia , Proteínas do Tecido Nervoso , Receptor de Fator de Crescimento Neural/metabolismo , Receptores de Fator de Crescimento Neural/metabolismo , Proteínas tau/metabolismoRESUMO
The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10-5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.
Assuntos
Proteína C9orf72/genética , Degeneração Lobar Frontotemporal/diagnóstico , Degeneração Lobar Frontotemporal/genética , Genes Ligados ao Cromossomo X/genética , Estudo de Associação Genômica Ampla/métodos , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Degeneração Lobar Frontotemporal/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
INTRODUCTION: Dementia with Lewy bodies (DLB) may represent a diagnostic challenge, since its clinical picture overlaps with other dementia. Two toolkits have been developed to aid the clinician to diagnose DLB: the Lewy Body Composite Risk Score (LBCRS) and the Assessment Toolkit for DLB (AT-DLB). We aim to evaluate the reliability of these two questionnaires, and their ability to enhance the interpretation of the international consensus diagnostic criteria. METHODS: LBCRS and AT-DLB were distributed to 135 Italian Neurological Centers for Cognitive Decline and Dementia (CDCDs), with the indication to administer them to all patients with dementia referred within the subsequent 3 months. We asked to subsequently apply consensus criteria for DLB diagnosis, to validate the diagnostic accuracy of the two toolkits. RESULTS: A total of 23 Centers joined the study; 1854 patients were enrolled. We found a prevalence of possible or probable DLB of 13% each (26% total), according to the consensus criteria. LBCRS toolkit showed good reliability, with a Cronbach alpha of 0.77, stable even after removing variables from the construct. AT-DLB toolkit Cronbach alpha was 0.52 and, after the subtraction of the "cognitive fluctuation" criterion, was only 0.31. Accuracy, sensitivity, and specificity were higher for LBCRS vs. AT-DLB. However, when simultaneously considered in the logistic models, AT-DLB showed a better performance (p < 0.001). Overall, the concordance between LBCRS positive and AT-DLB possible/probable was of 78.02% CONCLUSIONS: In a clinical setting, the LBCRS and AT-DLB questionnaires have good accuracy for DLB diagnosis.
Assuntos
Doença de Alzheimer , Doença por Corpos de Lewy , Doença de Alzheimer/diagnóstico , Diagnóstico Diferencial , Humanos , Itália , Doença por Corpos de Lewy/diagnóstico , Reprodutibilidade dos TestesRESUMO
Genetic discoveries related to Alzheimer's disease and other dementias have been performed using either large cohorts of affected subjects or multiple individuals from the same pedigree, therefore disregarding mutations in the context of healthy groups. Moreover, a large portion of studies so far have been performed on individuals of European ancestry, with a remarkable lack of epidemiological and genomic data from underrepresented populations. In the present study, 70 single-point mutations on the APP gene in a publicly available genetic dataset that included 2504 healthy individuals from 26 populations were scanned, and their distribution was analyzed. Furthermore, after gametic phase reconstruction, a pairwise comparison of the segments surrounding the mutations was performed to reveal patterns of haplotype sharing that could point to specific cross-population and cross-ancestry admixture events. Eight mutations were detected in the worldwide dataset, with several of them being specific for a single individual, population, or macroarea. Patterns of segment sharing reflected recent historical events of migration and admixture possibly linked to colonization campaigns. These observations reveal the population dynamics of the considered APP mutations in worldwide human groups and support the development of ancestry-informed screening practices for the improvement of precision and personalized approaches to neurodegeneration and dementia.
Assuntos
Precursor de Proteína beta-Amiloide , Genética Populacional , Migração Humana , Humanos , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Mutação , Mutação Puntual , Dinâmica PopulacionalRESUMO
BACKGROUND: Dentatorubral-pallidoluysian atrophy is a hereditary neurodegenerative disease prevalently reported in Japan but rare in Caucasians. The objective of this study was to reconstruct the pedigree of Italian dentatorubral-pallidoluysian atrophy familial cases describing their clinical features. METHODS: We investigated 6 apparently unrelated dentatorubral-pallidoluysian atrophy families comprising a total of 51 affected individuals: 13 patients were clinically examined, and for 38 patients clinical data were collected from clinical sources. The dentatorubral-pallidoluysian atrophy diagnosis was genetically confirmed in 18 patients. Genealogical data from historical archives were analyzed. RESULTS: All 6 families were unified in a large pedigree deriving from a founder couple originating from Monte San Giuliano (Italy) in the late 1500s, with 51 affected subjects over the last 4 generations. Wide phenotypical variability in age at onset and clinical features was confirmed. Epilepsy was more frequent in juvenile cases than in late adults, with cognitive/psychiatric and motor disorders observed regardless of age at onset. CONCLUSIONS: We have described the largest Caucasian dentatorubral-pallidoluysian atrophy pedigree from a single founder couple. The introduction of the dentatorubral-pallidoluysian atrophy gene in Italy could have arisen as a result of trade relationships between the Spanish or Portuguese and the Japanese in the 1500s. © 2019 International Parkinson and Movement Disorder Society.
Assuntos
Efeito Fundador , Mutação/genética , Epilepsias Mioclônicas Progressivas/epidemiologia , Epilepsias Mioclônicas Progressivas/genética , Adolescente , Adulto , Idoso , Criança , Epilepsia/complicações , Epilepsia/epidemiologia , Família , Feminino , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Epilepsias Mioclônicas Progressivas/psicologia , Testes Neuropsicológicos , Linhagem , Repetições de Trinucleotídeos , População Branca , Adulto JovemRESUMO
Inherited mutations in the Prion protein (PrP), encoded by the PRNP gene, have been associated with autosomal dominant neurodegenerative disorders, such as Creutzfeldt-Jacob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and Fatal Familial Insomnia (FFI). Notably, PRNP mutations have also been described in clinical pictures resembling other neurodegenerative diseases, such as frontotemporal dementia. Regarding the pathogenesis, it has been observed that these point mutations are located in the C-terminal region of the PRNP gene and, currently, the potential significance of the N-terminal domain has largely been underestimated. The purpose of this report is to review and provide current insights into the pathogenic mechanisms of PRNP mutations, emphasizing the differences between the C- and N-terminal regions and focusing, in particular, on the lesser-known flexible N-terminal, for which recent biophysical evidence has revealed a physical interaction with the globular C-terminal domain of the cellular prion protein (PrPC).
Assuntos
Síndrome de Creutzfeldt-Jakob/genética , Demência Frontotemporal/genética , Doença de Gerstmann-Straussler-Scheinker/genética , Mutação , Proteínas PrPC/genética , Proteínas Priônicas/genética , Sítios de Ligação , Encéfalo/metabolismo , Encéfalo/patologia , Cátions Bivalentes , Cobre/química , Cobre/metabolismo , Síndrome de Creutzfeldt-Jakob/metabolismo , Síndrome de Creutzfeldt-Jakob/patologia , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Expressão Gênica , Doença de Gerstmann-Straussler-Scheinker/metabolismo , Doença de Gerstmann-Straussler-Scheinker/patologia , Humanos , Proteínas PrPC/química , Proteínas PrPC/metabolismo , Proteínas Priônicas/química , Proteínas Priônicas/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Zinco/química , Zinco/metabolismoRESUMO
In the central nervous system, cholesterol is critical to maintain membrane plasticity, cellular function, and synaptic integrity. In recent years, much attention was focused on the role of cholesterol in brain since a breakdown of cholesterol metabolism has been associated with different diseases. Brain-derived neurotrophic factor (BDNF) was previously reported to elicit cholesterol biosynthesis and promote the accumulation of presynaptic proteins in cholesterol-rich lipid rafts, but no data are available on its ability to modulate physiological mechanisms involved in cholesterol homeostasis. Major aim of this research was to investigate whether BDNF influences cholesterol homeostasis, focusing on the effect of the neurotrophin on Apolipoprotein E (ApoE) synthesis, cholesterol efflux from astrocytes and cholesterol incorporation into neurons. Our results show that BDNF significantly stimulates cholesterol efflux by astrocytes, as well as ATP binding cassette A1 (ABCA1) transporter and ApoE expression. Conversely, cholesterol uptake in neurons was downregulated by BDNF. This effect was associated with the increase of Liver X Receptor (LXR)-beta expression in neuron exposed to BDNF. The level of apoptosis markers, that is, cleaved caspase 3 and poly ADP ribose polymerase (PARP), was found increased in neurons treated with high cholesterol, but significantly lower when the cells were exposed to cholesterol in the presence of BDNF, thus suggesting a neuroprotective role of the neurotrophin, likely through its reducing effect of neuronal cholesterol uptake. Interestingly, cholesterol stimulates BDNF production by neurons. Overall, our findings evidenced a novel role of BDNF in the modulation of ApoE and cholesterol homeostasis in glial and neuronal cells.
Assuntos
Apolipoproteínas E/biossíntese , Astrócitos/metabolismo , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Colesterol/metabolismo , Homeostase/efeitos dos fármacos , Neurônios/metabolismo , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Receptores X do Fígado/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Pessoa de Meia-Idade , Modelos Biológicos , Neurônios/efeitos dos fármacos , Córtex Pré-Frontal/metabolismoRESUMO
Maintenance of electric potential and synaptic transmission are energetically demanding tasks that neuronal metabolism must continually satisfy. Inability to fulfil these energy requirements leads to the development of neurodegenerative disorders, including Alzheimer's disease. A prominent feature of Alzheimer's disease is in fact neuronal glucose hypometabolism. Thus understanding the fine control of energetic metabolism might help to understand neurodegenerative disorders. Recent research has indicated that a novel class of signalling molecules, the inositol pyrophosphates, act as energy sensors. They are able to alter the balance between mitochondrial oxidative phosphorylation and glycolytic flux, ultimately affecting the cellular level of ATP. The neuronal inositol pyrophosphate synthesis relies on the activity of the neuron enriched inositol hexakisphosphate kinase 3 (IP6K3) enzyme. To verify an involvement of inositol pyrophosphate signalling in neurodegenerative disorders, we performed tagging single nucleotide polymorphism (SNP) analysis of the IP6K3 gene in patients with familial and sporadic late onset Alzheimer's disease (LOAD). Two SNPs in the 5'-flanking promoter region of the IP6K3 gene were found to be associated with sporadic LOAD. Characterizing the functionality of the two polymorphisms by luciferase assay revealed that one of them (rs28607030) affects IP6K3 promoter activity, with the G allele showing an increased activity. As the same allele has a beneficial effect on disease risk, this may be related to upregulation of IP6K3 expression, with a consequent increase in inositol pyrophosphate synthesis. In conclusion, we provide the first evidence for a contribution of genetic variability in the IP6K3 gene to LOAD pathogenesis.
Assuntos
Doença de Alzheimer/enzimologia , Doença de Alzheimer/genética , Fosfotransferases (Aceptor do Grupo Fosfato)/genética , Região 5'-Flanqueadora , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/etiologia , Estudos de Casos e Controles , Linhagem Celular , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Células HEK293 , Humanos , Técnicas In Vitro , Desequilíbrio de Ligação , Masculino , Fosfotransferases (Aceptor do Grupo Fosfato)/metabolismo , Polimorfismo de Nucleotídeo Único , Regiões Promotoras GenéticasRESUMO
The G4C2-repeat expansion in C9orf72 is a common cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 transcription is reduced in expansion carriers implicating haploinsufficiency as one of the disease mechanisms. Indeed, our recent ALS study revealed that the expansion was associated with hypermethylation of the CpG-island (5'of the repeat) in DNA samples obtained from different tissues (blood, brain and spinal cord). However, the link between FTLD and methylation of the CpG-island is unknown. Hence, we investigated the methylation profile of the same CpG-island by bisulfite sequencing of DNA obtained from blood of 34 FTLD expansion carriers, 166 FTLD non-carriers and 103 controls. Methylation level was significantly higher in FTLD expansion carriers than non-carriers (P = 7.8E-13). Our results were confirmed by two methods (HhaI-assay and sequencing of cloned bisulfite PCR products). Hypermethylation occurred only in carriers of an allele with >50 repeats, and was not detected in non-carriers or individuals with an intermediate allele (22-43 repeats). As expected, the position/number of methylated CpGs was concordant between the sense and anti-sense DNA strand, suggesting that it is a stable epigenetic modification. Analysis of the combined ALS and FTLD datasets (82 expansion carriers) revealed that the degree of methylation of the entire CpG-island or contribution of specific CpGs (n = 26) is similar in both syndromes, with a trend towards a higher proportion of ALS patients with a high methylation level (P = 0.09). In conclusion, we demonstrated that hypermethylation of the CpG-island 5'of the G4C2-repeat is expansion-specific, but not syndrome-specific (ALS versus FTLD).
Assuntos
Ilhas de CpG , Metilação de DNA , Expansão das Repetições de DNA , Degeneração Lobar Frontotemporal/genética , Proteínas/genética , Idade de Início , Idoso , Esclerose Lateral Amiotrófica/genética , Proteína C9orf72 , Conjuntos de Dados como Assunto , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNARESUMO
The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.
Assuntos
Doença de Alzheimer/genética , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Idade de Início , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Linhagem Celular , Endossomos/metabolismo , Variação Genética , Haplótipos , Humanos , Íntrons , Modelos Genéticos , Especificidade de Órgãos , Polimorfismo de Nucleotídeo Único , Nexinas de Proteases , Receptores de Superfície Celular/metabolismo , Proteínas de Transporte Vesicular/metabolismoRESUMO
Kufs disease, an adult-onset neuronal ceroid lipofuscinosis, is challenging to diagnose and genetically heterogeneous. Mutations in CLN6 were recently identified in recessive Kufs disease presenting as progressive myoclonus epilepsy (Type A), whereas the molecular basis of cases presenting with dementia and motor features (Type B) is unknown. We performed genome-wide linkage mapping of two families with recessive Type B Kufs disease and identified a single region on chromosome 11 to which both families showed linkage. Exome sequencing of five samples from the two families identified homozygous and compound heterozygous missense mutations in CTSF within this linkage region. We subsequently sequenced CTSF in 22 unrelated individuals with suspected recessive Kufs disease, and identified an additional patient with compound heterozygous mutations. CTSF encodes cathepsin F, a lysosomal cysteine protease, dysfunction of which is a highly plausible candidate mechanism for a storage disorder like ceroid lipofuscinosis. In silico modeling suggested the missense mutations would alter protein structure and function. Moreover, re-examination of a previously published mouse knockout of Ctsf shows that it recapitulates the light and electron-microscopic pathological features of Kufs disease. Although CTSF mutations account for a minority of cases of type B Kufs, CTSF screening should be considered in cases with early-onset dementia and may avoid the need for invasive biopsies.
Assuntos
Catepsina F/genética , Mutação de Sentido Incorreto , Lipofuscinoses Ceroides Neuronais/genética , Adulto , Animais , Células do Corno Anterior/patologia , Estudos de Casos e Controles , Catepsina F/metabolismo , Mapeamento Cromossômico , Consanguinidade , Análise Mutacional de DNA , Exoma , Feminino , Estudos de Associação Genética , Humanos , Escore Lod , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Modelos Moleculares , Lipofuscinoses Ceroides Neuronais/enzimologia , Lipofuscinoses Ceroides Neuronais/patologia , Linhagem , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Análise de Sequência de RNARESUMO
The most common cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a G4C2-repeat expansion in C9orf72. However, the lower limit for pathological repeats has not been established and expansions with different sizes could have different pathological consequences. One of the implicated disease mechanisms is haploinsufficiency. Previously, we identified expansion-specific hypermethylation at the 5' CpG-island near the G4C2-repeat, but only in a fraction of carriers (up to 36 %). Here, we tested the hypothesis that the G4C2-repeat itself could be the main site of methylation. To evaluate (G4C2)n -methylation, we developed a novel assay, which was validated by an independent methylation-sensitive restriction enzyme assay. Notably, both assays are qualitative but not quantitative. Blood DNA was available for 270 unrelated individuals, including 71 expansion carriers. In addition, we investigated blood DNA from family members of 16 probands, and 38 DNA samples from multiple tissues of 10 expansion carriers. Finally, we tested DNA from different tissues of an ALS patient carrying a somatically unstable 90-repeat. We demonstrated that the G4C2-expansion is generally methylated in unrelated carriers of alleles >50 repeats (97 %), while small (<22 repeats) or intermediate (22-90 repeats) alleles were completely unmethylated. The presence of (G4C2)n -methylation does not separate the C9orf72-phenotypes (ALS vs. ALS/FTLD vs. FTLD), but has the potential to predict large vs. intermediate repeat length. Our results suggest that (G4C2)n -methylation might sometimes spread to the 5'-upstream region, but not vice versa. It is stable over time, since (G4C2)n -methylation was detected in carriers with a wide range of ages (24-74 years). It was identified in both blood and brain tissues for the same individual, implying its potential use as a biomarker. Furthermore, our findings may open up new perspectives for studying disease mechanisms, such as determining whether methylated and unmethylated repeats have the same ability to form a G-quadruplex configuration.
Assuntos
Esclerose Lateral Amiotrófica/genética , Ilhas de CpG , Metilação de DNA , Expansão das Repetições de DNA , Degeneração Lobar Frontotemporal/genética , Proteínas/genética , Idoso , Alelos , Proteína C9orf72 , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mapeamento por Restrição/métodos , Análise de Sequência de DNARESUMO
An increasing number of hereditary neurodegenerative diseases, including autosomal-dominant Alzheimer disease (AD), familial autosomal-dominant frontotemporal dementia (FTD), and heritable Lewy body disease (LBD) have been defined at the molecular level in recent years, making it possible to determine the genotype before the onset of symptoms. The identification of deterministic genes for these common adult-onset genetic diseases is moving the field of genetic counseling toward a new and challenging direction. With the identification of genes associated with AD and FTD, there is considerable interest in the clinical application of genetic information in genetic counseling and testing. Progress in the genetics of dementing disorders and the availability of clinical tests for practicing physicians therefore increases the need for a better understanding of the multifaceted issues associated with genetic testing. The aims of this systematic review are: (1) to underline the need to consider a genetic etiology of AD, FTD, and LBD; (2) to provide clinicians with information necessary to effectively translate genetic diagnosis into clinical practice; and (3) to highlight gaps and uncertainties in the field which will need to be addressed by future research.
Assuntos
Demência/genética , Doenças Neurodegenerativas/genética , Aconselhamento Genético , Predisposição Genética para Doença , Testes Genéticos , HumanosRESUMO
The Forkhead box P2 (FOXP2) is an evolutionary conserved transcription factor involved in the maintenance of neuronal networks, implicated in language disorders. Some evidence suggests a possible link between FOXP2 genetic variability and frontotemporal dementia (FTD) pathology and related endophenotypes. To shed light on this issue, we analysed the association between single-nucleotide polymorphisms (SNPs) in FOXP2 and FTD in 113 patients and 223 healthy controls. In addition, we investigated SNPs in two putative targets of FOXP2, CNTNAP2, Contactin-associated protein-like 2 and PRNP, prion protein genes. Overall, 27 SNPs were selected by a tagging approach. FOXP2-rs17213159-C/T resulted associated with disease risk (OR = 2.16, P = 0.0004), as well as with age at onset and severity of dementia. Other FOXP2 markers were associated with semantic and phonological fluency scores, cognitive levels (MMSE) and neuropsychological tests. Associations with language, cognitive and brain atrophy measures were found with CNTNAP2 and PRNP genetic variability. Overall, although preliminary, results here presented suggest an influence of regulatory pathways centred on FOXP2 as a molecular background of FTD affecting neurological function of multiple brain areas.
RESUMO
BACKGROUND: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. METHODS: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. RESULTS: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. CONCLUSIONS: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.
Assuntos
Demência Frontotemporal , Masculino , Humanos , Feminino , Progranulinas/genética , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Virulência , Mutação/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genéticaRESUMO
Therapeutic strategies in Alzheimer's disease (AD) must take into account the characteristics of elderly people, who often have somatic comorbidities. Moreover, demented patients are more frequently frailer than older people. They have a higher number of admissions to hospital, a greater prevalence of complications and an increased risk of death. Therapeutic decisions for these patients have to be approached cautiously: aging, a more elevated comorbidity/polytherapy index and frailty contribute to enhance the risk of pharmacological adverse events and drug interactions. The aim of the present study was to focus on risk-benefit profile of pharmacological therapy for AD in relation to somatic comorbidities that often affect these patients. A Medline search (from 2001 to 2012) was performed using as key words dementia, Alzheimer's disease, drug treatment, somatic comorbidities, side effects/adverse events and elderly. Cholinesterase inhibitors (ChEIs) and memantine represent the main pharmacological strategies effective in reducing the progression of cognitive decline and functional loss in AD. Many conditions very common in the elderly may restrict the use of ChEIs and/or treatment efficacy in AD patients. Memantine has a good efficacy and tolerability profile with better safety in pulmonary, cardiovascular and central nervous system comorbidities compared to ChEIs. Drug interactions with memantine are also more favorable since they concern mostly drugs not commonly used in the elderly. Only a careful evaluation of the associated somatic diseases, taking into account different drugs safety indexes and tolerability, can lead to personalized treatment management, in order to maximize drug efficacy and optimize quality of life.