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1.
Immunity ; 42(6): 1185-96, 2015 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-26084028

RESUMEN

The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity. Mutations in AIRE cause a rare autosomal-recessive disease, autoimmune polyendocrine syndrome type 1 (APS-1), distinguished by multi-organ autoimmunity. We have identified multiple cases and families with mono-allelic mutations in the first plant homeodomain (PHD1) zinc finger of AIRE that followed dominant inheritance, typically characterized by later onset, milder phenotypes, and reduced penetrance compared to classical APS-1. These missense PHD1 mutations suppressed gene expression driven by wild-type AIRE in a dominant-negative manner, unlike CARD or truncated AIRE mutants that lacked such dominant capacity. Exome array analysis revealed that the PHD1 dominant mutants were found with relatively high frequency (>0.0008) in mixed populations. Our results provide insight into the molecular action of AIRE and demonstrate that disease-causing mutations in the AIRE locus are more common than previously appreciated and cause more variable autoimmune phenotypes.


Asunto(s)
Análisis Mutacional de ADN/métodos , Genes Dominantes/genética , Mutación/genética , Poliendocrinopatías Autoinmunes/genética , Factores de Transcripción/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Autoinmunidad/genética , Niño , Preescolar , Femenino , Frecuencia de los Genes , Humanos , Masculino , Repeticiones de Microsatélite/genética , Datos de Secuencia Molecular , Noruega , Especificidad de Órganos/genética , Linaje , Penetrancia , Fenotipo , Federación de Rusia , Adulto Joven , Proteína AIRE
2.
Age Ageing ; 53(2)2024 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-38342753

RESUMEN

BACKGROUND: In-hospital delirium is associated with adverse outcomes and is underdiagnosed, limiting research and clinical follow-up. OBJECTIVE: To compare the incidence of in-hospital delirium determined by chart-based review of electronic medical records (D-CBR) with delirium discharge diagnoses (D-DD). Furthermore, to identify differences in symptoms, treatments and delirium triggers between D-CBR and D-DD. METHOD: The community-based cohort included 2,115 participants in the Hordaland Health Study born between 1925 and 1927. Between 2018 and 2022, we retrospectively reviewed hospital electronic medical records from baseline (1997-99) until death prior to 2023. D-DD and D-CBR were validated using The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for delirium. RESULTS: Of the 2,115 participants, 638 had in-hospital delirium. The incidence rate (IR) of D-CBR was 29.8 [95% confidence interval 28, 32] per 1,000 person-years, whereas the IR by D-DD was 3.4 [2.8, 4.2]. The IR ratio was 9.14 (P < 0.001). Patients who received pharmacological treatment for delirium (n = 121, odds ratio (OR) 3.4, [2.1, 5.4], P < 0.001), who were affected by acute memory impairment (n = 149, OR 2.8, [1.8, 4.5], P < 0.001), or change in perception (n = 137, OR 2.9, [1.8, 4.6] P < 0.001) had higher odds for D-DD. In contrast, post-operative cases (OR 0.2, [0.1, 0.4], P < 0.001) had lower odds for D-DD. CONCLUSION: Underdiagnosis of in-hospital delirium was a major issue in our study, especially in less severe delirium cases. Our findings emphasise the need for integrating systematic delirium diagnostics and documentation into hospital admission and discharge routines.


Asunto(s)
Delirio , Humanos , Delirio/diagnóstico , Delirio/epidemiología , Delirio/terapia , Estudios Retrospectivos , Factores de Riesgo , Hospitales , Registros Médicos
3.
Acta Neuropathol ; 135(3): 409-425, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29270838

RESUMEN

Mitochondrial complex I deficiency occurs in the substantia nigra of individuals with Parkinson's disease. It is generally believed that this phenomenon is caused by accumulating mitochondrial DNA damage in neurons and that it contributes to the process of neurodegeneration. We hypothesized that if these theories are correct, complex I deficiency should extend beyond the substantia nigra to other affected brain regions in Parkinson's disease and correlate tightly with neuronal mitochondrial DNA damage. To test our hypothesis, we employed a combination of semiquantitative immunohistochemical analyses, Western blot and activity measurements, to assess complex I quantity and function in multiple brain regions from an extensively characterized population-based cohort of idiopathic Parkinson's disease (n = 18) and gender and age matched healthy controls (n = 11). Mitochondrial DNA was assessed in single neurons from the same areas by real-time PCR. Immunohistochemistry showed that neuronal complex I deficiency occurs throughout the Parkinson's disease brain, including areas spared by the neurodegenerative process such as the cerebellum. Activity measurements in brain homogenate confirmed a moderate decrease of complex I function, whereas Western blot was less sensitive, detecting only a mild reduction, which did not reach statistical significance at the group level. With the exception of the substantia nigra, neuronal complex I loss showed no correlation with the load of somatic mitochondrial DNA damage. Interestingly, α-synuclein aggregation was less common in complex I deficient neurons in the substantia nigra. We show that neuronal complex I deficiency is a widespread phenomenon in the Parkinson's disease brain which, contrary to mainstream theory, does not follow the anatomical distribution of neurodegeneration and is not associated with the neuronal load of mitochondrial DNA mutation. Our findings suggest that complex I deficiency in Parkinson's disease can occur independently of mitochondrial DNA damage and may not have a pathogenic role in the neurodegenerative process.


Asunto(s)
Encéfalo/metabolismo , Complejo I de Transporte de Electrón/deficiencia , Mitocondrias/metabolismo , Enfermedades Mitocondriales/metabolismo , Neuronas/metabolismo , Enfermedad de Parkinson/metabolismo , Anciano , Anciano de 80 o más Años , Encéfalo/patología , Daño del ADN , ADN Mitocondrial/metabolismo , Complejo I de Transporte de Electrón/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias/patología , Enfermedades Mitocondriales/patología , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/patología , Neuronas/patología , Enfermedad de Parkinson/patología , Estudios Prospectivos , Agregación Patológica de Proteínas/metabolismo , Agregación Patológica de Proteínas/patología , alfa-Sinucleína/metabolismo
4.
Mov Disord ; 33(10): 1591-1600, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-30256453

RESUMEN

BACKGROUND: Mitochondrial dysfunction plays a key role in PD, but the underlying molecular mechanisms remain unresolved. We hypothesized that the disruption of mitochondrial function in PD is primed by rare, protein-altering variation in nuclear genes controlling mitochondrial structure and function. OBJECTIVE: The objective of this study was to assess whether genetic variation in genes associated with mitochondrial function influences the risk of idiopathic PD. METHODS: We employed whole-exome sequencing data from 2 independent cohorts of clinically validated idiopathic PD and controls, the Norwegian ParkWest cohort (n = 411) and the North American Parkinson's Progression Markers Initiative (n = 640). We applied burden-based and variance-based collapsing methods to assess the enrichment of rare, nonsynonymous, and damaging genetic variants on genes, exome-wide, and on a comprehensive set of mitochondrial pathways, defined as groups of genes controlling specific mitochondrial functions. RESULTS: Using the sequence kernel association test, we detected a significant polygenic enrichment of rare, nonsynonymous variants in the gene-set encoding the pathway of mitochondrial DNA maintenance. Notably, this was the strongest association in both cohorts and survived multiple testing correction (ParkWest P = 6.3 × 10-3 , Parkinson's Progression Markers Initiative P = 6.9 × 10-5 , metaanalysis P = 3.2 × 10-6 ). CONCLUSIONS: Our results show that the enrichment of rare inherited variation in the pathway controlling mitochondrial DNA replication and repair influences the risk of PD. We propose that this polygenic enrichment contributes to the impairment of mitochondrial DNA homeostasis, thought to be a key mechanism in the pathogenesis of PD, and explains part of the disorder's "missing heritability." © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
ADN Mitocondrial/genética , Predisposición Genética a la Enfermedad/genética , Variación Genética/genética , Mitocondrias/genética , Enfermedad de Parkinson/genética , Transducción de Señal/genética , Estudios de Cohortes , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Metaanálisis como Asunto , América del Norte , Noruega
5.
Mov Disord ; 32(11): 1594-1599, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28861893

RESUMEN

BACKGROUND: Whether antidiabetic glitazone drugs protect against Parkinson's disease remains controversial. Although a single clinical trial showed no evidence of disease modulation, retrospective studies suggest that a disease-preventing effect may be plausible. The objective of this study was to examine if the use of glitazone drugs is associated with a lower incidence of PD among diabetic patients. METHODS: We compared the incidence of PD between individuals with diabetes who used glitazones, with or without metformin, and individuals using only metformin in the Norwegian Prescription Database. This database contains all prescription drugs dispensed for the entire Norwegian population. We identified 94,349 metformin users and 8396 glitazone users during a 10-year period and compared the incidence of PD in the 2 groups using Cox regression survival analysis, with glitazone exposure as a time-dependent covariate. RESULTS: Glitazone use was associated with a significantly lower incidence of PD compared with metformin-only use (hazard ratio, 0.72; 95% confidence interval, 0.55-0.94; P = 0.01). CONCLUSIONS: The use of glitazones is associated with a decreased risk of incident PD in populations with diabetes. Further studies are warranted to confirm and understand the role of glitazones in neurodegeneration. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Metformina/farmacología , Enfermedad de Parkinson/prevención & control , Tiazolidinedionas/farmacología , Adulto , Anciano , Anciano de 80 o más Años , Bases de Datos Factuales/estadística & datos numéricos , Diabetes Mellitus Tipo 2/epidemiología , Prescripciones de Medicamentos/estadística & datos numéricos , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Enfermedad de Parkinson/epidemiología
6.
Eur J Neurol ; 22(2): 328-333, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25311247

RESUMEN

BACKGROUND AND PURPOSE: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a devastating, hereditary white matter (WM) disorder with heterogeneous neuropsychiatric features. Colony stimulating factor 1 receptor (CSF1R) mutations were looked for in primary progressive multiple sclerosis (PPMS) patients and the clinical features of a family with a novel CSF1R mutation are reported. METHODS: CSF1R exons 12-22 in a cohort of 220 PPMS patients from the Swedish and Norwegian national multiple sclerosis registries were sequenced. RESULTS: One patient had a novel mutation, c.2562T>A; p.Asn854Lys, in the CSF1R gene. Her symptoms started at the age of 29 years with insidious onset of pyramidal weakness in the left leg. The cerebrospinal fluid examination showed four intrathecal immunoglobulin G bands. A magnetic resonance imaging scan performed 4 years after symptom onset demonstrated patchy deep WM lesions. She was diagnosed as having PPMS and treated with intramuscular interferon beta 1a. Due to slow disease progression, the development of memory decline and cerebellar signs, she was given subcutaneous interferon beta 1a without any benefit. The updated pedigree indicated that five siblings also had the CSF1R gene mutation; one was diagnosed with PPMS. Six more distant relatives also had a neurological disorder; four were clinically diagnosed with PPMS. CONCLUSIONS: Our study indicates that a chronic course of HDLS may mimic PPMS. Genetic testing for CSF1R gene mutations in PPMS cases with a positive family history of neurological disorders may establish the diagnosis of HDLS.


Asunto(s)
Esclerosis Múltiple Crónica Progresiva/genética , Receptor de Factor Estimulante de Colonias de Macrófagos/genética , Sistema de Registros , Adulto , Exones , Femenino , Humanos , Leucoencefalopatías/diagnóstico , Leucoencefalopatías/genética , Esclerosis Múltiple Crónica Progresiva/diagnóstico , Mutación , Noruega , Linaje , Fenotipo , Hermanos , Suecia
7.
Brain ; 136(Pt 8): 2393-404, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23625061

RESUMEN

The role of mitochondria in the pathogenesis of neurodegeneration is an area of intense study. It is known that defects in proteins involved in mitochondrial quality control can cause Parkinson's disease, and there is increasing evidence linking mitochondrial dysfunction, and particularly mitochondrial DNA abnormalities, to neuronal loss in the substantia nigra. Mutations in the catalytic subunit of polymerase gamma are among the most common causes of mitochondrial disease and owing to its role in mitochondrial DNA homeostasis, polymerase gamma defects are often considered a paradigm for mitochondrial diseases generally. Yet, despite this, parkinsonism is uncommon with polymerase gamma defects. In this study, we investigated structural and functional changes in the substantia nigra of 11 patients with polymerase gamma encephalopathy. We characterized the mitochondrial DNA abnormalities and examined the respiratory chain in neurons of the substantia nigra. We also investigated nigrostriatal integrity and function using a combination of post-mortem and in vivo functional studies with dopamine transporter imaging and positron emission tomography. At the cellular level, dopaminergic nigral neurons of patients with polymerase gamma encephalopathy contained a significantly lower copy number of mitochondrial DNA (depletion) and higher levels of deletions than normal control subjects. A selective and progressive complex I deficiency was seen and this was associated with a severe and progressive loss of the dopaminergic neurons of the pars compacta. Dopamine transporter imaging and positron emission tomography showed that the degree of nigral neuronal loss and nigrostriatal depletion were severe and appeared greater even than that seen in idiopathic Parkinson's disease. Despite this, however, none of our patients showed any signs of parkinsonism. The additional presence of both thalamic and cerebellar dysfunction in our patients suggested that these may play a role in counteracting the effects of basal ganglia dysfunction and prevent the development of clinical parkinsonism.


Asunto(s)
Cuerpo Estriado/patología , ADN Polimerasa Dirigida por ADN/genética , Enfermedades Mitocondriales/genética , Degeneración Nerviosa/genética , Trastornos Parkinsonianos/genética , Sustancia Negra/patología , Adolescente , Adulto , Cuerpo Estriado/metabolismo , ADN Polimerasa gamma , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , ADN Polimerasa Dirigida por ADN/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Mutación , Degeneración Nerviosa/patología , Neuronas/metabolismo , Neuronas/patología , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Sustancia Negra/metabolismo
9.
Prog Neurobiol ; 236: 102603, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38604582

RESUMEN

The STRAT-PARK initiative aims to provide a platform for stratifying Parkinson's disease (PD) into biological subtypes, using a bottom-up, multidisciplinary biomarker-based and data-driven approach. PD is a heterogeneous entity, exhibiting high interindividual clinicopathological variability. This diversity suggests that PD may encompass multiple distinct biological entities, each driven by different molecular mechanisms. Molecular stratification and identification of disease subtypes is therefore a key priority for understanding and treating PD. STRAT-PARK is a multi-center longitudinal cohort aiming to recruit a total of 2000 individuals with PD and neurologically healthy controls from Norway and Canada, for the purpose of identifying molecular disease subtypes. Clinical assessment is performed annually, whereas biosampling, imaging, and digital and neurophysiological phenotyping occur every second year. The unique feature of STRAT-PARK is the diversity of collected biological material, including muscle biopsies and platelets, tissues particularly useful for mitochondrial biomarker research. Recruitment rate is ∼150 participants per year. By March 2023, 252 participants were included, comprising 204 cases and 48 controls. STRAT-PARK is a powerful stratification initiative anticipated to become a global research resource, contributing to personalized care in PD.


Asunto(s)
Enfermedad de Parkinson , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Biomarcadores , Canadá , Estudios de Cohortes , Estudios Longitudinales , Noruega , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/fisiopatología , Medicina de Precisión/métodos
12.
iScience ; 26(3): 106278, 2023 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-36936793

RESUMEN

Replenishing nicotinamide adenine dinucleotide (NAD) via supplementation of nicotinamide riboside (NR) has been shown to confer neuroprotective effects in models of aging and neurodegenerative diseases, including Parkinson's disease (PD). Although generally considered safe, concerns have been raised that NR supplementation could impact methylation dependent reactions, including DNA methylation, because of increased production and methylation dependent breakdown of nicotinamide (NAM). We investigated the effect of NR supplementation on DNA methylation in a double blinded, placebo-controlled trial of 29 human subjects with PD, in blood cells and muscle tissue. Our results show that NR had no impact on DNA methylation homeostasis, including individuals with common pathogenic mutations in the MTHFR gene known to affect one-carbon metabolism. Pathway and methylation variance analyses indicate that there might be minor regulatory responses to NR. We conclude that short-term therapy with high-dose NR for up to 30 days has no deleterious impact on methylation homeostasis.

13.
Nat Commun ; 14(1): 7793, 2023 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-38016950

RESUMEN

Nicotinamide adenine dinucleotide (NAD) replenishment therapy using nicotinamide riboside (NR) shows promise for Parkinson's disease (PD) and other neurodegenerative disorders. However, the optimal dose of NR remains unknown, and doses exceeding 2000 mg daily have not been tested in humans. To evaluate the safety of high-dose NR therapy, we conducted a single-center, randomized, placebo-controlled, double-blind, phase I trial on 20 individuals with PD, randomized 1:1 on NR 1500 mg twice daily (n = 10) or placebo (n = 10) for four weeks. The trial was conducted at the Department of Neurology, Haukeland University Hospital, Bergen, Norway. The primary outcome was safety, defined as the frequency of moderate and severe adverse events. Secondary outcomes were tolerability defined as frequency of mild adverse events, change in the whole blood and urine NAD metabolome, and change in the clinical severity of PD, measured by MDS-UPDRS. All 20 participants completed the trial. The trial met all prespecified outcomes. NR therapy was well tolerated with no moderate or severe adverse events, and no significant difference in mild adverse events. NR therapy was associated with clinical improvement of total MDS-UPDRS scores. However, this change was also associated with a shorter interval since the last levodopa dose. NR greatly augmented the blood NAD metabolome with up to 5-fold increase in blood NAD+ levels. While NR-recipients exhibited a slight initial rise in serum homocysteine levels, the integrity of the methyl donor pool remained intact. Our results support extending the dose range of NR in phase II clinical trials to 3000 mg per day, with appropriate safety monitoring. Clinicaltrials.gov identifier: NCT05344404.


Asunto(s)
Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , NAD , Niacinamida , Compuestos de Piridinio/efectos adversos , Método Doble Ciego
15.
NPJ Parkinsons Dis ; 8(1): 19, 2022 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-35236852

RESUMEN

Epidemiological studies of Parkinson's disease (PD) show variable and partially conflicting findings with regard to incidence, prevalence, and mortality. These differences are commonly attributed to technical and methodological factors, including small sample sizes, differences in diagnostic practices, and population heterogeneity. We leveraged the Norwegian Prescription Database, a population-based registry of drug prescriptions dispensed from Norwegian pharmacies to assess the incidence, prevalence, and mortality of PD in Norway. The diagnosis of PD was defined based on the prescription of dopaminergic drugs for the indication of PD over a continuous time. During 2004-2017, 12,229 males and 9831 females met our definition for PD diagnosis. PD prevalence increased over the observation period, with larger changes observed in the older age groups. Incidence and prevalence of PD increased with age, peaking at 85 years. The male/female prevalence ratio was 1.5 across all ages, whereas the incidence ratio increased with age, from 1.4 in those 60 years, to 2.03 among those >90 years. While PD mortality was generally higher than that of the general population, mortality odds ratios decreased with age, approaching 1.0 among individuals >90 years old. When adjusted for the sex-specific mortality of the general population, the mortality among females with PD was equal to or higher than the mortality among males with PD. Our findings demonstrate that the epidemiological features of PD, including sex-differences, are age and time-period dependent and indicate that sex differences in PD mortality are unlikely to stem from disease-specific negative impact of survival in males.

16.
Cell Metab ; 34(3): 396-407.e6, 2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-35235774

RESUMEN

We conducted a double-blinded phase I clinical trial to establish whether nicotinamide adenine dinucleotide (NAD) replenishment therapy, via oral intake of nicotinamide riboside (NR), is safe, augments cerebral NAD levels, and impacts cerebral metabolism in Parkinson's disease (PD). Thirty newly diagnosed, treatment-naive patients received 1,000 mg NR or placebo for 30 days. NR treatment was well tolerated and led to a significant, but variable, increase in cerebral NAD levels-measured by 31phosphorous magnetic resonance spectroscopy-and related metabolites in the cerebrospinal fluid. NR recipients showing increased brain NAD levels exhibited altered cerebral metabolism, measured by 18fluoro-deoxyglucose positron emission tomography, and this was associated with mild clinical improvement. NR augmented the NAD metabolome and induced transcriptional upregulation of processes related to mitochondrial, lysosomal, and proteasomal function in blood cells and/or skeletal muscle. Furthermore, NR decreased the levels of inflammatory cytokines in serum and cerebrospinal fluid. Our findings nominate NR as a potential neuroprotective therapy for PD, warranting further investigation in larger trials.


Asunto(s)
NAD , Enfermedad de Parkinson , Suplementos Dietéticos , Humanos , NAD/metabolismo , Niacinamida/análogos & derivados , Niacinamida/farmacología , Niacinamida/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Compuestos de Piridinio/uso terapéutico
17.
PLoS One ; 16(9): e0256602, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34492069

RESUMEN

OBJECTIVE: Whether use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of incident Parkinson's disease (PD) remains unresolved. Here, we employed the Norwegian Prescription Database to examine whether NSAID use is associated with a lower incidence of PD. METHODS: We compared the incidence of PD among users of NSAIDs in a population-based retrospective study using the Norwegian Prescription Database from 2004 to 2017. In total 7580 PD patients were identified using dopaminergic therapy over time as proxy for PD diagnosis. Analyses were performed with minimum 90 and 365 defined daily dose (DDD) NSAID exposure, respectively. Time-dependent Cox regression model and a binary logistic regression analysis with a 5-year lag until PD diagnosis were performed for all NSAIDs. RESULTS: There was overall no decrease in incidence of PD among NSAID users compared to controls. Using a minimum of 90 or 365 DDD threshold of exposure produced similar results. Analysis of individual NSAIDs did not show difference in PD incidence compared to controls Age-specific incidence rates of PD were comparable to reported age-specific incidence rates in previous studies. INTERPRETATION: Our findings provide no evidence that cumulative high exposure to NSAIDs affects the risk of developing PD.


Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Inflamación/tratamiento farmacológico , Enfermedad de Parkinson/epidemiología , Anciano , Anciano de 80 o más Años , Antiinflamatorios no Esteroideos/efectos adversos , Bases de Datos Factuales , Femenino , Humanos , Inflamación/complicaciones , Inflamación/epidemiología , Inflamación/patología , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/patología , Prescripciones , Modelos de Riesgos Proporcionales , Factores de Riesgo
18.
Mol Neurodegener ; 16(1): 31, 2021 05 05.
Artículo en Inglés | MEDLINE | ID: mdl-33947435

RESUMEN

BACKGROUND: Parkinson's disease (PD) is a complex, age-related neurodegenerative disorder of largely unknown etiology. PD is strongly associated with mitochondrial respiratory dysfunction, which can lead to epigenetic dysregulation and specifically altered histone acetylation. Nevertheless, and despite the emerging role of epigenetics in age-related brain disorders, the question of whether aberrant histone acetylation is involved in PD remains unresolved. METHODS: We studied fresh-frozen brain tissue from two independent cohorts of individuals with idiopathic PD (n = 28) and neurologically healthy controls (n = 21). We performed comprehensive immunoblotting to identify histone sites with altered acetylation levels in PD, followed by chromatin immunoprecipitation sequencing (ChIP-seq). RNA sequencing data from the same individuals was used to assess the impact of altered histone acetylation on gene expression. RESULTS: Immunoblotting analyses revealed increased acetylation at several histone sites in PD, with the most prominent change observed for H3K27, a marker of active promoters and enhancers. ChIP-seq analysis further indicated that H3K27 hyperacetylation in the PD brain is a genome-wide phenomenon with a strong predilection for genes implicated in the disease, including SNCA, PARK7, PRKN and MAPT. Integration of the ChIP-seq with transcriptomic data from the same individuals revealed that the correlation between promoter H3K27 acetylation and gene expression is attenuated in PD patients, suggesting that H3K27 acetylation may be decoupled from transcription in the PD brain. Strikingly, this decoupling was most pronounced among nuclear-encoded mitochondrial genes, corroborating the notion that impaired crosstalk between the nucleus and mitochondria is involved in the pathogenesis of PD. Our findings independently replicated in the two cohorts. CONCLUSIONS: Our findings strongly suggest that aberrant histone acetylation and altered transcriptional regulation are involved in the pathophysiology of PD. We demonstrate that PD-associated genes are particularly prone to epigenetic dysregulation and identify novel epigenetic signatures associated with the disease.


Asunto(s)
Química Encefálica , Código de Histonas , Histonas/metabolismo , Enfermedad de Parkinson/genética , Procesamiento Proteico-Postraduccional , Transcripción Genética , Acetilación , Antiparkinsonianos/farmacología , Secuencia de Bases , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Regulación de la Expresión Génica/efectos de los fármacos , Genoma Humano , Humanos , Neuronas/efectos de los fármacos , Enfermedad de Parkinson/metabolismo , Corteza Prefrontal/química , Sirtuina 1/análisis , Sirtuina 2/análisis , Sirtuina 3/análisis
19.
Mov Disord ; 25(13): 2156-63, 2010 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-20669305

RESUMEN

Genealogical investigation of a large Norwegian family (F04) with autosomal dominant parkinsonism has identified 18 affected family members over four generations. Genetic studies have revealed a novel pathogenic LRRK2 mutation c.4309 A>C (p.Asn1437His) that co-segregates with disease manifestation (LOD = 3.15, θ = 0). Affected carriers have an early age at onset (48 ± 7.7 SD years) and are clinically asymmetric and levodopa responsive. The variant was absent in 623 Norwegian control subjects. Further screening of patients from the same population identified one additional affected carrier (1 of 692) with familial parkinsonism who shares the same haplotype. The mutation is located within the Roc domain of the protein and enhances GTP-binding and kinase activity, further implicating these activities as the mechanisms that underlie LRRK2-linked parkinsonism.


Asunto(s)
Asparagina/genética , Histidina/genética , Mutación/genética , Enfermedad de Parkinson/genética , Proteínas Serina-Treonina Quinasas/genética , Anciano , Anciano de 80 o más Años , Línea Celular Transformada , Femenino , Pruebas Genéticas , Guanosina Trifosfato/metabolismo , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Masculino , Persona de Mediana Edad , Noruega , Enfermedad de Parkinson/diagnóstico , Proteínas Serina-Treonina Quinasas/metabolismo , Escalas de Valoración Psiquiátrica , Tomografía Computarizada de Emisión de Fotón Único/métodos , Transfección/métodos
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