RESUMEN
BACKGROUND: Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by an expanded GAA repeat in the first intron of the FXN gene. OBJECTIVE: The aim of this study was to analyze leukocyte telomeres length (LTL) in FRDA to verify the possible relationships between LTL and disease progression. We investigated LTL in a cohort of FRDA biallelic patients (n = 61), heterozygous (n = 29), and age-matched healthy subjects (n = 87). METHODS: LTL was measured by real-time polymerase chain reaction quantitative analysis (qPCR). RESULTS: The results showed that before 35 years of age, leukocyte telomeres were longer in patients than in controls, whereas the reverse applies in patients above 36 years of age. Interestingly, LTL was greater than controls at any age in heterozygous subjects. This picture mirrors what has been previously observed in vitro in FRDA cultured fibroblasts, showing significantly longer telomeres at early passages because of activation of an alternative lengthening of telomeres (ALT)-like mechanism, but showing accelerated telomere shortening as population doubling increases. GAA1 repeat length is positively correlated with the LTL and negatively correlated with the age at blood sampling. The relationship of LTL with clinical parameters (cardiomyopathy, diabetes, dependence on a wheelchair) was also analyzed. Significantly shorter leukocyte telomeres were associated with the presence of cardiomyopathy, but not with diabetes and the dependence on a wheelchair. CONCLUSIONS: Overall, the present study indicates that telomere length analysis in FRDA may be a relevant biomarker for following the stages of the disease. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
RESUMEN
Huntington's disease (HD) is characterized by clinical motor impairment (e.g., involuntary movements, poor coordination, parkinsonism), cognitive deficits, and psychiatric symptoms. An inhered expansion of the CAG triplet in the huntingtin gene causing a pathogenic gain-of-function of the mutant huntingtin (mHTT) protein has been identified. In this review, we focus on known biomarkers (e.g., mHTT, neurofilament light chains) and on new biofluid biomarkers that can be quantified in plasma or peripheral blood mononuclear cells from mHTT carriers. Circulating biomarkers may fill current unmet needs in HD management: better stratification of patients amenable to etiologic treatment; the initiation of preventive treatment in premanifest HD; and the identification of peripheral pathogenic central nervous system cascades.
Asunto(s)
Trastornos del Conocimiento , Disfunción Cognitiva , Enfermedad de Huntington , Humanos , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , Leucocitos Mononucleares/metabolismo , Trastornos del Conocimiento/etiología , Biomarcadores , Disfunción Cognitiva/complicaciones , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismoRESUMEN
The identification of biomarkers for neurodegenerative disorders such as Huntington's disease (HD) is crucial for monitoring disease progression and therapeutic trial outcomes, especially in the pre-manifest disease stage (pre-HD). In a previous study, we observed that leukocyte telomere length (LTL) was strongly correlated with the estimated time to clinical onset in pre-HD subjects. To validate this hypothesis, we designed a follow-up study in which we analyzed LTL in 45 pre-HD stage subjects at baseline (T0) and then again after clinical onset at follow-up (T1); the follow-up interval was about 3 years, and the CAG range was 39-51 repeats; 90 peripheral blood mononuclear cell samples (PBMCs) were obtained from the Enroll-HD biorepository. In pre-HD subjects at T0, LTL was significantly reduced by 22% compared to the controls and by 14% from T0 at T1. No relationship was observed between the LTL and CAG numbers in subjects carrying different CAG repeats at T0 and at T1, suggesting that LTL reduction occurs independently of CAG number in pre-HD subjects. ROC curve analysis was used to test the validity of LTL as a potential biomarker of HD progression and showed that LTL measurement is extremely accurate in discriminating pre-HD subjects from the controls and even pre-HD from manifest HD, thus yielding a robust prognostic value in pre-HD subjects.
Asunto(s)
Enfermedad de Huntington , Humanos , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/genética , Estudios de Seguimiento , Telómero/genética , Leucocitos Mononucleares , Leucocitos , BiomarcadoresRESUMEN
Plasma small RNAs have been recently explored as biomarkers in Huntington's disease (HD). We performed an exploratory study on nine HD patients, eight healthy subjects (HS), and five psychiatric patients (PP; to control for iatrogenic confounder effects) through an Affymetrix-Gene-Chip-miRNA-Array. We validated the results in an independent population of 23 HD, 15 pre-HD, 24 PP, 28 Alzheimer's disease (AD) patients (to control the disease-specificity) and 22 HS through real-time PCR. The microarray results showed higher levels of U13 small nucleolar RNA (SNORD13) in HD patients than controls (fold change 1.54, p = 0.003 HD vs. HS, and 1.44, p = 0.0026 HD vs. PP). In the validation population, a significant increase emerged with respect to both pre-HD and the control groups (p < 0.0001). SNORD13 correlated with the status of the mutant huntingtin carrier (r = 0.73; p < 0.001) and the disease duration (r = 0.59; p = 0.003). The receiver operating characteristic (ROC) curve analysis showed the high accuracy of SNORD13 in discriminating HD patients from other groups (AUC = 0.963). An interactome and pathway analysis on SNORD13 revealed enrichments for factors relevant to HD pathogenesis. We report the unprecedented finding of a potential disease-specific role of SNORD13 in HD. It seems to peripherally report a 'tipping point' in the pathogenic cascade at the neuronal level.
Asunto(s)
Enfermedad de Huntington , MicroARNs , Humanos , Enfermedad de Huntington/genética , Enfermedad de Huntington/metabolismo , ARN Nucleolar Pequeño/genética , Proyectos Piloto , Proteína Huntingtina/genética , BiomarcadoresRESUMEN
SCA1, SCA2, and SCA3 are the most common forms of SCAs among the polyglutamine disorders, which include Huntington's Disease (HD). We investigated the relationship between leukocyte telomere length (LTL) and the phenotype of SCA1, SCA2, and SCA3, comparing them with HD. The results showed that LTL was significantly reduced in SCA1 and SCA3 patients, while LTL was significantly longer in SCA2 patients. A significant negative relationship between LTL and age was observed in SCA1 but not in SCA2 subjects. LTL of SCA3 patients depend on both patient's age and disease duration. The number of CAG repeats did not affect LTL in the three SCAs. Since LTL is considered an indirect marker of an inflammatory response and oxidative damage, our data suggest that in SCA1 inflammation is present already at an early stage of disease similar to in HD, while in SCA3 inflammation and impaired antioxidative processes are associated with disease progression. Interestingly, in SCA2, contrary to SCA1 and SCA3, the length of leukocyte telomeres does not reduce with age. We have observed that SCAs and HD show a differing behavior in LTL for each subtype, which could constitute relevant biomarkers if confirmed in larger cohorts and longitudinal studies.
RESUMEN
We investigated the possible influence of TERC and TERT genetic variation and leukocyte telomere length (LTL) on human lifespan. Four polymorphisms of TERT and three polymorphisms of TERC were examined in a sample of elderly subjects (70â»100 years). After nine years of follow-up, mortality data were collected, and sub-samples of long-lived/not long-lived were defined. TERT VNTR MNS16A L/L genotype and TERT rs2853691 A/G or G/G genotypes were found to be associated with a significantly higher risk to die before the age of 90 years, and with a significantly lower age at death. The association between lifespan and LTL at baseline was analyzed in a subsample of 163 subjects. Age at baseline was inversely associated with LTL (p < 0.0001). Mean LTL was greater in the subjects still living than in those no longer living at follow-up (0.79 T/S ± 0.09 vs 0.63 T/S ± 0.08, p < 0.0001). Comparison of age classes showed that, among the 70â»79-year-olds, the difference in mean LTL between those still living and those no longer living at follow-up was greater than among the 80â»90-year-olds. Our data provide evidence that shorter LTL at baseline may predict a shorter lifespan, but the reliability of LTL as a lifespan biomarker seems to be limited to a specific age (70â»79 years).
Asunto(s)
Longevidad/genética , Polimorfismo de Nucleótido Simple , Telomerasa/genética , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Repeticiones de Microsatélite , ARN/genética , Homeostasis del TelómeroRESUMEN
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded CAG repeat. Though symptom onset commonly occurs at midlife and inversely correlates with the CAG repeat expansion, age at clinical onset and progression rate are variable. In the present study we investigated the relationship between leukocyte telomere length (LTL) and HD development. LTL was measured by real-time PCR in manifest HD patients (HD, nâ¯=â¯62), pre-manifest HD patients (pre-HD, nâ¯=â¯38), and age-matched controls (nâ¯=â¯76). Significant LTL differences were observed between the three groups (pâ¯<â¯.0001), with LTL values in the order: HDâ¯<â¯pre-HDâ¯<â¯controls. The relationship between LTL and age was different in the three groups. An inverse relationship between mean LTL and CAG repeat number was found in the pre-HD (pâ¯=â¯.03). The overall data seem to indicate that after age 30â¯years, LT begins to shorten markedly in pre-HD patients according to CAG number and increasing age, up to the values observed in HD. This very suggestive picture allowed us to hypothesize that in pre-manifest HD, LTL could be a measure of time to clinical HD onset. The possible use of LTL as a reliable biomarker to track HD development and progression was evaluated and discussed.
Asunto(s)
Enfermedad de Huntington/patología , Leucocitos/fisiología , Acortamiento del Telómero/fisiología , Telómero/genética , Expansión de Repetición de Trinucleótido/genética , Adulto , Factores de Edad , Anciano , Análisis de Varianza , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Humanos , Proteína Huntingtina/genética , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Análisis de Regresión , Adulto JovenRESUMEN
Numerous studies have reported an association between shortened leukocyte telomere length (LTL) and increased risk of Alzheimer's disease (AD). In this study we investigated the relationship between LTL and AD development, including in the analysis patients with amnestic mild cognitive impairment (aMCI), a clinical entity considered prodromal of AD. LTL (T/S ratio) was measured in patients with AD (n=61) or aMCI (n=46), and compared with LTL of age-matched controls (n=56). Significant LTL differences were observed between controls, aMCI and AD patients (p<0.0001), with mean LTL values (±s.d) in the order: AD patients (0.70±0.15)Asunto(s)
Enfermedad de Alzheimer/genética
, Enfermedad de Alzheimer/psicología
, Cognición
, Disfunción Cognitiva/genética
, Disfunción Cognitiva/psicología
, Leucocitos/química
, Acortamiento del Telómero
, Telómero/genética
, Anciano
, Anciano de 80 o más Años
, Enfermedad de Alzheimer/sangre
, Enfermedad de Alzheimer/diagnóstico
, Estudios de Casos y Controles
, Disfunción Cognitiva/sangre
, Disfunción Cognitiva/diagnóstico
, Progresión de la Enfermedad
, Femenino
, Humanos
, Modelos Lineales
, Masculino
, Pruebas de Estado Mental y Demencia
, Persona de Mediana Edad
, Pruebas Neuropsicológicas
, Factores de Riesgo
RESUMEN
Mild cognitive impairment (MCI) is the transition stage between the normal aging process and dementia itself. The most common clinical phenotype is amnestic MCI (aMCI) [subtypes: single domain (sMCI) and multiple domains (mMCI)], which is considered prodromal to Alzheimer's disease (AD). The APOE (apolipoprotein E) e4 allele is the most important genetic risk factor for AD, but its association with MCI onset and conversion to AD is controversial. In this follow-up study of 88 aMCI patients (68% sMCI and 32% mMCI at baseline), we examined APOE genotypes and plasma levels in relation to MCI development and progression based on their clinical/cognitive data obtained at baseline and follow-up assessment (mean follow-up time = 6.6 ± 3.4 years). A control sample (n = 164) was collected in previous investigations. The overall conversion rate to mMCI or AD was 52.2%. The APOE e4 allele was associated with a higher risk of developing MCI (OR: 2.23; 95%CI: 1.22-4.08). The conversion rate in the e4 allele carriers (32% of the sample) was 71%, and the e4 allele was associated with a higher risk of conversion to mMCI/AD (OR: 4.1; 95%CI: 1.2-13.6). APOE e2 allele carriers were 7% (all sMCI) and none progressed to mMCI/AD. Among MCI subjects, e4 carriers had the lowest plasma apoE levels (37.8 ± 12.5 mg/L), and e2 carriers had the highest (78.6 ± 38.1 mg/L). APOE e4 is a risk allele for the development and progression of aMCI, the APOE e2 allele seems to be protective, and apoE levels associated to them are an integral part of their action. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Apolipoproteínas E/genética , Disfunción Cognitiva/genética , Anciano , Anciano de 80 o más Años , Alelos , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/genética , Apolipoproteínas E/sangre , Apolipoproteínas E/metabolismo , Trastornos del Conocimiento/genética , Disfunción Cognitiva/sangre , Demencia/genética , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/genética , Genotipo , Heterocigoto , Humanos , Masculino , Pruebas Neuropsicológicas , Factores de RiesgoRESUMEN
Family history of dementia (FH) is a recognized risk factor for developing late-onset Alzheimer's disease (AD). We asked whether having FH increases AD risk and influences disease severity (age at onset and cognitive impairment) in 420 AD patients and 109 controls with (FH+) or without (FH-). The relationships of APOE and other AD risk genes with FH were analyzed as well. The proportion of APOE e4 allele carriers was higher among the FH+ than the FH- AD patients (49.6% vs. 38.9%; P = 0.04). The distribution of the risk genotypes of nine AD susceptibility genes previously examined (CHAT, CYP17, CYP19, ESR1, FSHR, P53, P73, P21, PPARG) did not differ between the FH+ and the FH- AD patients, indicating that none contributed significantly to familial clustering of disease. FH was associated with an increased AD risk (odds ratio [OR] 2.71, 95% confidence interval [CI] 1.44-5.09; P = 0.002) independent of carrying the APOE e4 allele (OR 2.61, 95%CI 1.53-4.44; P = 0.0004). Having a first-degree relative or a parent with dementia was significantly associated with AD risk (OR 2.9, 95%CI 1.3-6.4; P = 0.009 and OR 2.7, 95%CI 1.1-6.2; P = 0.02) but having a sibling with dementia was not (OR 1.7, 95%CI 0.2 to 14.7; P = 0.6). Among the FH+ AD patients, having one or both parents affected seemed to raise the risk of earlier onset age (P = 0.02) and greater cognitive impairment (P = 0.02) than having only an affected sibling, whereas having two or more affected relatives did not.
Asunto(s)
Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/etiología , Demencia/complicaciones , Progresión de la Enfermedad , Edad de Inicio , Anciano , Apolipoproteínas E/genética , Estudios de Casos y Controles , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/genética , Familia , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Factores de RiesgoRESUMEN
Evolutionary theories of aging predict an antagonistic relationship between fertility and life span in humans, but the genetic basis of this phenomenon is not clear. The variation of three genes in steroid hormone metabolism--CYP17 (rs743572), HSD17B1 (rs 605059), and COMT (rs4680)--was examined to elucidate the genetic basis of the relationship between fertility and life span. A sample of 277 individuals (mean age, 82.9 years) was recruited in 2000. On the basis of mortality data collected in 2009, the sample was divided into two groups of subjects surviving to over 90 years (long-lived) or not (controls). Fertility data (number of children) were collected in the same sample. The HSD17B1 AA genotype was found to be significantly associated (p = 0.0085) with longevity only in the females (estimated odds ratio = 3.77). Because the HSD17B1 AA genotype was also associated with a higher number of children (5.3 ± 2.1) than the other genotypes (p = 0.006), we may infer that HSD17B1 genotypes could exert a positive pleiotropic action on longevity and fertility. CYP17 and COMT gene variation did not influence either life span or fertility. We then searched the literature for genes studied in relation to both reproduction and aging. A review of the studies showed a pleiotropic action for six out of 16 genes and revealed that genes may exert positive, or negative, or antagonistic pleiotropic actions. These potential actions may be modified by such environmental factors such as changing reproductive behaviors, which seem to be able to mitigate or enhance a gene's phenotypic effects.
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Catecol O-Metiltransferasa/genética , Estradiol Deshidrogenasas/genética , Hormonas/metabolismo , Longevidad/genética , Polimorfismo de Nucleótido Simple/genética , Reproducción/genética , Esteroide 17-alfa-Hidroxilasa/genética , Esteroides/metabolismo , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Fertilidad/genética , Frecuencia de los Genes/genética , Humanos , MasculinoRESUMEN
The greater predisposition of women to Alzheimer's disease (AD), owing to the decrease in postmenopausal estrogen, may be influenced by polymorphic variation in genes regulating estrogen metabolism (e.g., COMT) and estrogen biosynthesis (e.g., CYP17). In order to better understand how the estrogen pathway genetic variation might affect AD onset, we conducted a case-control study of two single nucleotide polymorphisms (SNPs) of these two genes (COMT rs4680 and CYP17 rs743572) in a sample of AD patients of Italian origin. The COMT allele and genotype were found associated neither with AD onset nor with parameters of AD severity, such as cognitive impairment, age at onset, or disease duration. In contrast, CYP17 was found to affect the age at disease onset mainly in males and, as compared with noncarriers, people carrying the A2 (C) allele had a 2.2-fold increased risk for AD. These findings suggest that the CYP17 A2 allele influences AD susceptibility in a sex-specific way by acting not only on AD risk but also on the age at disease onset, an important parameter of AD severity.
Asunto(s)
Enfermedad de Alzheimer/genética , Catecol O-Metiltransferasa/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Esteroide 17-alfa-Hidroxilasa/genética , Edad de Inicio , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Análisis de Varianza , Apolipoproteínas E/genética , Trastornos del Conocimiento/genética , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Genotipo , Humanos , Italia , Masculino , Escala del Estado MentalRESUMEN
ARCHAEA-ExPRESs is an mRNA modification technology that makes use of components derived from the Archaeon Methanocaldococcus jannaschii, namely the tRNA splicing endonuclease (MJ-EndA) and its natural substrate, the bulge-helix-bulge (BHB) structure (1). These components can perform both cis- and trans-splicing in cellular and animal models and may provide a convenient way to modulate gene expression using components independent of cellular regulatory networks. To use MJ-EndA in stable expression mammalian systems, we developed variants characterized by high efficiency and sustainable in vivo activity. The MJ-EndA variants were created by the introduction of proper localization signals followed by mutagenesis and direct selection in mammalian cells. Of note, enzyme selection used an in vivo selection method based on puromycin resistance conferred to cells by BHB-mediated intron splicing from an out-of-frame puromycin N-acetyl transferase (PAC) gene. This approach yielded several endonuclease variants, the best of which showed 40-fold higher activity compared to the parental enzyme and stable processing of 30% of the target mRNA. Notably, these variants showed complete compatibility with long-term expression in mammalian cells, suggesting that they may be usefully applied in functional genomics and genetically modified animal models.
Asunto(s)
Archaea/enzimología , Archaea/genética , Proteínas Arqueales/metabolismo , Endonucleasas/metabolismo , Empalme del ARN/genética , Proteínas Arqueales/genética , Western Blotting , Línea Celular , Endonucleasas/genética , Técnica del Anticuerpo Fluorescente , Humanos , Reacción en Cadena de la PolimerasaRESUMEN
tRNA splicing is essential for the formation of tRNAs and therefore for gene expression. A circularly permuted sequence of an amber-suppressor pre-tRNA gene was inserted into the sequence encoding the mouse NEMO protein. We demonstrated that, in mouse cells, the hybrid pre-tRNA/pre-mRNAs can be spliced precisely at the sites of the pre-tRNA intron. This splicing reaction produces functional tRNAs that suppress amber codons as well as translatable mRNAs that sustain the NF-kappaB activation pathway. The RNA molecules extracted from mouse cells were amplified by RT-PCR, and their sequences were determined, confirming the identity of the splice junctions. We then applied the Archaea-express technology, in which an archaeal RNA endonuclease is expressed in mouse cells. We show that both the endogenous eukaryal endonuclease and the archaeal one cleave the hybrid pre-tRNA/pre-mRNAs in the same manner with an additive effect.