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1.
Alzheimers Dement ; 19(7): 2805-2815, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36576960

RESUMEN

INTRODUCTION: Patients with familial early-onset dementia (EOD) pose a unique opportunity for gene identification studies. METHODS: We present the phenotype and whole-exome sequencing (WES) study of an autosomal dominant EOD family. Candidate genes were examined in a set of dementia cases and controls (n = 3712). Western blotting was conducted of the wild-type and mutant protein of the final candidate. RESULTS: Age at disease onset was 60 years (range 56 to 63). The phenotype comprised mixed amnestic and behavioral features, and parkinsonism. Cerebrospinal fluid and plasma biomarkers, and a positron emission tomography amyloid study suggested Alzheimer's disease. WES and the segregation pattern pointed to a nonsense mutation in the TRIM25 gene (p.C168*), coding for an E3 ubiquitin ligase, which was absent in the cohorts studied. Protein studies supported a loss-of-function mechanism. DISCUSSION: This study supports a new physiopathological mechanism for brain amyloidosis. Furthermore, it extends the role of E3 ubiquitin ligases dysfunction in the development of neurodegenerative diseases. HIGHLIGHTS: A TRIM25 nonsense mutation (p.C168*) is associated with autosomal dominant early-onset dementia and parkinsonism with biomarkers suggestive of Alzheimer's disease. TRIM25 protein studies support that the mutation exerts its effect through loss of function. TRIM25, an E3 ubiquitin ligase, is known for its role in the innate immune response but this is the first report of association with neurodegeneration. The role of TRIM25 dysfunction in development of amyloidosis and neurodegeneration merits a new line of research.


Asunto(s)
Enfermedad de Alzheimer , Amiloidosis , Demencia , Trastornos Parkinsonianos , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Codón sin Sentido , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Trastornos Parkinsonianos/diagnóstico por imagen , Trastornos Parkinsonianos/genética , Proteínas Amiloidogénicas , Biomarcadores , Proteínas de Motivos Tripartitos/genética , Factores de Transcripción/genética
2.
Neurobiol Dis ; 156: 105421, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34118419

RESUMEN

Neurodegenerative disorders like frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are pathologically characterized by toxic protein deposition in the cytoplasm or nucleus of affected neurons and glial cells. Many of these aggregated proteins belong to the class of RNA binding proteins (RBP), and, when mutated, account for a significant subset of familial ALS and FTD cases. Here, we present first genetic evidence for the RBP gene RBM45 in the FTD-ALS spectrum. RBM45 shows many parallels with other FTD-ALS associated genes and proteins. Multiple lines of evidence have demonstrated that RBM45 is an RBP that, upon mutation, redistributes to the cytoplasm where it co-aggregates with other RBPs into cytoplasmic stress granules (SG), evolving to persistent toxic TDP-43 immunoreactive inclusions. Exome sequencing in two affected first cousins of a heavily affected early-onset dementia family listed a number of candidate genes. The gene with the highest pathogenicity score was the RBP gene RBM45. In the family, the RBM45 Arg183* nonsense mutation co-segregated in both affected cousins. Validation in an unrelated patient (n = 548) / control (n = 734) cohort identified an additional RBM45 Arg183* carrier with bvFTD on a shared 4 Mb haplotype. Transcript and protein expression analysis demonstrated loss of nuclear RBM45, suggestive of a loss-of-function disease mechanism. Further, two more ultra-rare VUS, one in the nuclear localization signal (NLS, p.Lys456Arg) in an ALS patient and one in the intrinsically disordered homo-oligomer assembly (HOA) domain (p.Arg314Gln) in a patient with nfvPPA were detected. Our findings suggest that the pathomechanisms linking RBM45 with FTD and ALS may be related to its loss of nuclear function as a mediator of mRNA splicing, cytoplasmic retention or its inability to form homo-oligomers, leading to aggregate formation with trapping of other RBPs including TDP-43, which may accumulate into persisted TDP-43 inclusions.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Secuenciación del Exoma/métodos , Demencia Frontotemporal/genética , Estudios de Asociación Genética/métodos , Proteínas del Tejido Nervioso/genética , Proteínas de Unión al ARN/genética , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Esclerosis Amiotrófica Lateral/diagnóstico , Esclerosis Amiotrófica Lateral/epidemiología , Bélgica/epidemiología , Estudios de Cohortes , Femenino , Demencia Frontotemporal/diagnóstico , Demencia Frontotemporal/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Linaje
3.
Neurobiol Dis ; 134: 104639, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31626953

RESUMEN

Stress granules (SGs) are dynamic membraneless compartments composed out of RNA-binding proteins (RBPs) and RNA molecules that assemble temporarily to allow the cell to cope with cellular stress by stalling mRNA translation and moving synthesis towards cytoprotective proteins. Aberrant SGs have become prime suspects in the nucleation of toxic protein aggregation in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Perturbed SG dynamics appears to be mediated by alterations in RNA binding proteins (RBP). Indeed, a growing number of FTD and/or ALS related RBPs coding genes (TDP43, FUS, EWSR1, TAF15, hnRNPA1, hnRNPA2B1, ATXN2, TIA1) have been identified to interfere with SG formation through mutation of their low-complexity domain (LCD), and thereby cause or influence disease. Interestingly, disease pathways associated to the C9orf72 repeat expansion, the leading genetic cause of the FTD-ALS spectrum, intersect with SG-mediated protein aggregate formation. In this review, we provide a comprehensive overview of known SG proteins and their genetic contribution to the FTD-ALS spectrum. Importantly, multiple LCD-baring RBPs have already been identified in FTD-ALS that have not yet been genetically linked to disease. These should be considered candidate genes and offer opportunities for gene prioritization when mining sequencing data of unresolved FTD and ALS. Further, we zoom into the current understanding of the molecular processes of perturbed RBP function leading to disturbed SG dynamics, RNA metabolism, and pathological inclusions. Finally, we indicate how these gained insights open new avenues for therapeutic strategies targeting phase separation and SG dynamics to reverse pathological protein aggregation and protect against toxicity.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Agregado de Proteínas , Agregación Patológica de Proteínas/genética , Agregación Patológica de Proteínas/patología , Animales , Humanos , Cuerpos de Inclusión/patología
4.
Acta Neuropathol ; 134(3): 475-487, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28447221

RESUMEN

Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad , Mutación , Polimorfismo de Nucleótido Simple , Adulto , Edad de Inicio , Anciano , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad
5.
Neurobiol Aging ; 76: 214.e11-214.e15, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30545478

RESUMEN

Frontotemporal lobar degeneration caused by GRN mutations is mainly associated with a TDP-43 type A proteinopathy. We present a family with autosomal dominant frontotemporal lobar degeneration caused by a novel GRN nonsense mutation (c.5G>A: p.Trp2*) in which the proband's brain also showed prominent glial tauopathy consistent with an aging-related tau astrogliopathy. Astrocytic tauopathy, 4R(+) and 3R(-) immunoreactive, was characterized by thorn-shaped astrocytes present in subpial, subependymal, and perivascular areas, and in gray matter; plus granular or fuzzy tau immunoreactivity in astrocytic processes in gray matter, either solitary or clustered in different regions. Some neurofibrillary tangles and pretangles, both 3R and 4R(+), were present in the medial temporal lobe but did not exhibit the characteristic distribution of Alzheimer's type pathology. This 4R-tau aging-related tau astrogliopathy is likely a co-occurring pathology, although an interaction between progranulin and tau proteins within the neurodegenerative process should not be ruled out.


Asunto(s)
Astrocitos/metabolismo , Astrocitos/patología , Codón sin Sentido/genética , Demencia Frontotemporal/genética , Estudios de Asociación Genética , Progranulinas/genética , Tauopatías/genética , Proteínas tau/metabolismo , Anciano , Anciano de 80 o más Años , Encéfalo/metabolismo , Encéfalo/patología , Femenino , Genes Dominantes/genética , Humanos , Masculino , Persona de Mediana Edad , Ovillos Neurofibrilares/genética , Ovillos Neurofibrilares/metabolismo , Tauopatías/metabolismo , Tauopatías/patología
6.
Neurobiol Aging ; 69: 293.e9-293.e11, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29886022

RESUMEN

We evaluated the genetic contribution of the T cell-restricted intracellular antigen-1 gene (TIA1) in a European cohort of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients. Exonic resequencing of TIA1 in 1120 patients (693 FTD, 341 ALS, 86 FTD-ALS) and 1039 controls identified in total 5 rare heterozygous missense variants, affecting the TIA1 low-complexity domain (LCD). Only 1 missense variant, p.Met290Thr, identified in a familial FTD patient with disease onset at 64 years, was absent from controls yet received a combined annotation-dependent depletion score of 11.42. By contrast, 3 of the 4 variants also detected in unaffected controls, p.Val294Glu, p.Gln318Arg, and p.Ala381Thr, had combined annotation-dependent depletion scores greater than 20. Our findings in a large European patient-control series indicate that variants in TIA1 are not a common cause of ALS and FTD. The observation of recurring TIA1 missense variants in unaffected individuals lead us to conclude that the exact genetic contribution of TIA1 to ALS and FTD pathogenesis remains to be further elucidated.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Demencia Frontotemporal/genética , Antígeno Intracelular 1 de las Células T/genética , Estudios de Cohortes , Femenino , Frecuencia de los Genes , Humanos , Masculino , Mutación Missense , Población Blanca/genética
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