-
1دورية أكاديمية
المؤلفون: Tanaka, MT, Miki, Y, Bettencourt, C, Ozaki, T, Tanji, K, Mori, F, Kakita, A, Wakabayashi, K
المصدر: Biochemical and Biophysical Research Communications , 623 pp. 170-175. (2022)
مصطلحات موضوعية: Autophagy, DEF8, Dementia with Lewy bodies, Parkinson's disease, Synucleinopathy, α-synuclein, Brain, Humans, Intracellular Signaling Peptides and Proteins, Lewy Bodies, Lewy Body Disease, Multiple System Atrophy, Parkinson Disease, Synucleinopathies, alpha-Synuclein
الوصف: Dysregulation of autophagy, one of the major processes through which abnormal proteins are degraded, is a cardinal feature of synucleinopathies, including Lewy body diseases [Parkinson's disease (PD) and dementia with Lewy bodies (DLB)] and multiple system atrophy (MSA), which are characterized by the presence of abnormal α-synuclein in neurons and glial cells. Although several research groups have reported that Rubicon family proteins can regulate autophagosome-lysosome fusion or positioning, little is known about their involvement in synucleinopathies. In the present study, by studying patients with PD (N = 8), DLB (N = 13), and MSA (N = 5) and controls (N = 16), we explored the involvement of Rubicon family proteins [Rubicon, Pacer and differentially expressed in FDCP8 (DEF8)] in synucleinopathies. Immunohistochemical analysis showed that not only brainstem-type Lewy bodies but also cortical Lewy bodies were immunoreactive for DEF8 in Lewy body diseases, whereas Rubicon and Pacer were detectable in only a few brainstem-type Lewy bodies in PD. Glial cytoplasmic inclusions in patients with MSA were not immunoreactive for Rubicon, Pacer or DEF8. Immunoblotting showed significantly increased protein levels of DEF8 in the substantia nigra and putamen of patients with PD and the temporal cortex of patients with DLB. In addition, the smear band of DEF8 appeared in the insoluble fraction where that of phosphorylated α-synuclein was detected. These findings indicate the involvement of DEF8 in the formation of Lewy bodies. Quantitative and qualitative alterations in DEF8 may reflect the dysregulation of autophagy in Lewy body diseases.
وصف الملف: text
العلاقة: https://discovery.ucl.ac.uk/id/eprint/10157092/1/Bettencourt_Accepted%20DEF8%20Manuscript.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10157092Test/
-
2دورية أكاديمية
المؤلفون: Hasan, R, Humphrey, J, Bettencourt, C, Newcombe, J, Lashley, T, Fratta, P, Raj, T
المصدر: Acta Neuropathologica , 143 pp. 383-401. (2022)
مصطلحات موضوعية: FTLD, FTD, RNA-seq, TDP-43, FTLD-TDP, Dementia, Gene expression, Transcriptomics
الوصف: Frontotemporal lobar degeneration (FTLD) is a group of heterogeneous neurodegenerative disorders affecting the frontal and temporal lobes of the brain. Nuclear loss and cytoplasmic aggregation of the RNA-binding protein TDP-43 represents the major FTLD pathology, known as FTLD-TDP. To date, there is no effective treatment for FTLD-TDP due to an incomplete understanding of the molecular mechanisms underlying disease development. Here we compared postmortem tissue RNA-seq transcriptomes from the frontal cortex, temporal cortex, and cerebellum between 28 controls and 30 FTLD-TDP patients to profile changes in cell-type composition, gene expression and transcript usage. We observed downregulation of neuronal markers in all three regions of the brain, accompanied by upregulation of microglia, astrocytes, and oligodendrocytes, as well as endothelial cells and pericytes, suggesting shifts in both immune activation and within the vasculature. We validate our estimates of neuronal loss using neuropathological atrophy scores and show that neuronal loss in the cortex can be mainly attributed to excitatory neurons, and that increases in microglial and endothelial cell expression are highly correlated with neuronal loss. All our analyses identified a strong involvement of the cerebellum in the neurodegenerative process of FTLD-TDP. Altogether, our data provides a detailed landscape of gene expression alterations to help unravel relevant disease mechanisms in FTLD.
وصف الملف: text
العلاقة: https://discovery.ucl.ac.uk/id/eprint/10143850/3/Lashley_FTLD-TDP%20Manuscript.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10143850Test/
-
3دورية أكاديمية
المؤلفون: Raposo, M, Bettencourt, C, Maciel, P, Gao, F, Ramos, A, Kazachkova, N, Vasconcelos, J, Kay, T, Rodrigues, AJ, Bettencourt, B, Bruges-Armas, J, Geschwind, D, Coppola, G, Lima, M
المصدر: Movement Disorders. 30(7)
مصطلحات موضوعية: Neurology & Neurosurgery, Clinical Sciences, Human Movement and Sports Sciences, Neurosciences
الوصف: Background: Machado-Joseph disease (or spinocerebellar ataxia type 3) is a late-onset polyglutamine neurodegenerative disorder caused by a mutation in the ATXN3 gene, which encodes for the ubiquitously expressed protein ataxin-3. Previous studies on cell and animal models have suggested that mutated ataxin-3 is involved in transcriptional dysregulation. Starting with a whole-transcriptome profiling of peripheral blood samples from patients and controls, we aimed to confirm abnormal expression profiles in Machado-Joseph disease and to identify promising up-regulated genes as potential candidate biomarkers of disease status. Methods: The Illumina Human V4-HT12 array was used to measure transcriptome-wide gene expression in peripheral blood samples from 12 patients and 12 controls. Technical validation and validation in an independent set of samples were performed by quantitative real-time polymerase chain reaction (PCR). Results: Based on the results from the microarray, twenty six genes, found to be up-regulated in patients, were selected for technical validation by quantitative real-time PCR (validation rate of 81% for the up-regulation trend). Fourteen of these were further tested in an independent set of 42 patients and 35 controls; 10 genes maintained the up-regulation trend (FCGR3B, CSR2RA, CLC, TNFSF14, SLA, P2RY13, FPR2, SELPLG, YIPF6, and GPR96); FCGR3B, P2RY13, and SELPLG were significantly up-regulated in patients when compared with controls. Conclusions: Our findings support the hypothesis that mutated ataxin-3 is associated with transcription dysregulation, detectable in peripheral blood cells. Furthermore, this is the first report suggesting a pool of up-regulated genes in Machado-Joseph disease that may have the potential to be used for fine phenotyping of this disease.
وصف الملف: application/pdf
الوصول الحر: https://escholarship.org/uc/item/8pq7j5cfTest
-
4دورية أكاديمية
المؤلفون: Gang, Q, Bettencourt, C, Brady, S, Holton, JL, Healy, EG, McConville, J, Morrison, PJ, Ripolone, M, Violano, R, Sciacco, M, Moggio, M, Mora, M, Mantegazza, R, Zanotti, S, Wang, Z, Yuan, Y, Liu, W-W, Beeson, D, Hanna, M, Houlden, H
المصدر: Annals of Clinical and Translational Neurology (2021) (In press).
مصطلحات موضوعية: CONGENITAL MYASTHENIC SYNDROME, SKELETAL-MUSCLE, CONSTITUTIVE ACTIVATION, MUTATIONS, ORAI1, STIM1, IDENTIFICATION, ASSOCIATION, EXPRESSION, FEATURES
الوصف: Objective: A group of genes have been reported to be associated with myopathies with tubular aggregates (TAs). Many cases with TAs still lack of genetic clarification. This study aims to explore the genetic background of cases with TAs in order to improve our knowledge of the pathogenesis of these rare pathological structures. Methods: Thirty-three patients including two family members with biopsy confirmed TAs were collected. Whole-exome sequencing was performed on 31 unrelated index patients and a candidate gene search strategy was conducted. The identified variants were confirmed by Sanger sequencing. The wild-type and the mutant p.Ala11Thr of ALG14 were transfected into human embryonic kidney 293 cells (HEK293), and western blot analysis was performed to quantify protein expression levels. Results: Eleven index cases (33%) were found to have pathogenic variant or likely pathogenic variants in STIM1, ORAI1, PGAM2, SCN4A, CASQ1 and ALG14. Among them, the c.764A>T (p.Glu255Val) in STIM1 and the c.1333G>C (p.Val445Leu) in SCN4A were novel. Western blot analysis showed that the expression of ALG14 protein was severely reduced in the mutant ALG14 HEK293 cells (p.Ala11Thr) compared with wild type. The ALG14 variants might be associated with TAs in patients with complex multisystem disorders. Interpretation: This study expands the phenotypic and genotypic spectrums of myopathies with TAs. Our findings further confirm previous hypothesis that genes related with calcium signalling pathway and N-linked glycosylation pathway are the main genetic causes of myopathies with TAs.
وصف الملف: text
العلاقة: https://discovery.ucl.ac.uk/id/eprint/10141180/1/Houlden_Genetic%20defects%20are%20common%20in%20myopathies%20with%20tubular%20aggregates.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10141180Test/
-
5دورية أكاديمية
المؤلفون: Raposo, M, Bettencourt, C, Melo, ARV, Ferreira, AF, Alonso, I, Silva, P, Vasconcelos, J, Kay, T, Saraiva-Pereira, ML, Costa, MD, Vilasboas-Campos, D, Bettencourt, BF, Bruges-Armas, J, Houlden, H, Heutink, P, Jardim, LB, Sequeiros, J, Maciel, P, Lima, M
المصدر: Neurobiology of Disease , 162 , Article 105578. (2021)
مصطلحات موضوعية: Age at onset, Genetic modifier, MJD, Polyglutamine disease, SCA3, Spinocerebellar ataxia
الوصف: Machado-Joseph disease (MJD/SCA3) is a neurodegenerative polyglutamine disorder exhibiting a wide spectrum of phenotypes. The abnormal size of the (CAG)n at ATXN3 explains ~55% of the age at onset variance, suggesting the involvement of other factors, namely genetic modifiers, whose identification remains limited. Our aim was to find novel genetic modifiers, analyse their epistatic effects and identify disease-modifying pathways contributing to MJD variable expressivity. We performed whole-exome sequencing in a discovery sample of four age at onset-concordant and four discordant first-degree relative pairs of Azorean patients, to identify candidate variants which genotypes differed for each discordant pair but were shared in each concordant pair. Variants identified by this approach were then tested in an independent multi-origin cohort of 282 MJD patients. Whole-exome sequencing identified 233 candidate variants, from which 82 variants in 53 genes were prioritized for downstream analysis. Eighteen disease-modifying pathways were identified; two of the most enriched pathways were relevant for the nervous system, namely the neuregulin signaling and the agrin interactions at neuromuscular junction. Variants at PARD3, NFKB1, CHD5, ACTG1, CFAP57, DLGAP2, ITGB1, DIDO1 and CERS4 modulate age at onset in MJD, with those identified in CFAP57, ACTG1 and DIDO1 showing consistent effects across cohorts of different geographical origins. Network analyses of the nine novel MJD modifiers highlighted several important molecular interactions, including genes/proteins previously related with MJD pathogenesis, namely between ACTG1/APOE and VCP/ITGB1. We describe novel pathways, modifiers, and their interaction partners, providing a broad molecular portrait of age at onset modulation to be further exploited as new disease-modifying targets for MJD and related diseases.
وصف الملف: text
العلاقة: https://discovery.ucl.ac.uk/id/eprint/10140428/1/Bettencourt_1-s2.0-S0969996121003272-main.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10140428Test/
-
6دورية أكاديمية
المؤلفون: Murthy, M, Cheng, YY, Holton, JL, Bettencourt, C
المصدر: Neuropathology and Applied Neurobiology , 47 (7) pp. 897-909. (2021)
مصطلحات موضوعية: DNA methylation, EWAS, Movement disorders, biomarkers, brain tissue, epigenetics, epigenomics, neurodegeneration, pathogenesis, therapy
الوصف: Neurodegenerative movement disorders (NMDs) are age dependent disorders that are characterised by the degeneration and loss of neurons, typically accompanied by pathological accumulation of different protein aggregates in the brain, which lead to motor symptoms. NMDs include Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, and Huntington's disease, among others. Epigenetic modifications are responsible for functional gene regulation during development, adult life, and ageing, and have progressively been implicated in complex diseases such as cancer, and more recently in neurodegenerative diseases, such as NMDs. DNA methylation is by far the most widely studied epigenetic modification and consists of the reversible addition of a methyl group to the DNA without changing the DNA sequence. Although this research field is still in its infancy in relation to NMDs, an increasing number of studies point towards a role for DNA methylation in disease processes. This review addresses recent advances in epigenetic and epigenomic research in NMDs, with a focus on human brain DNA methylation studies. We discuss the current understanding of the DNA methylation changes underlying these disorders, the potential for use of these DNA modifications in peripheral tissues as biomarkers in early disease detection, classification, and progression as well as a promising role in future disease management and therapy.
وصف الملف: text
العلاقة: https://discovery.ucl.ac.uk/id/eprint/10132429/7/Bettencourt_Neurodegenerative%20movement%20disorders-%20an%20epigenetics%20perspective%20and%20promise%20for%20the%20future_VoR.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10132429Test/
-
7دورية أكاديمية
المؤلفون: Verma, A, Ebanks, K, Fok, C-Y, Lewis, P, Bettencourt, C, Bandopadhyay, R
المصدر: Brain Research , 1765 , Article 147503. (2021)
الوصف: Mutations in LRRK2 are the most frequent cause of familial Parkinson’s disease (PD), with common LRRK2 non-coding variants also acting as risk factors for idiopathic PD. Currently, therapeutic agents targeting LRRK2 are undergoing advanced clinical trials in humans, however, it is important to understand the wider implications of LRRK2 targeted treatments given that LRRK2 is expressed in diverse tissues including the brain, kidney and lungs. This presents challenges to treatment in terms of effects on peripheral organ functioning, thus, protein interactors of LRRK2 could be targeted in lieu to optimize therapeutic effects. Herein an in-silico analysis of LRRK2 direct interactors in brain tissue from various brain regions was conducted along with a comparative analysis of the LRRK2 interactome in the brain, kidney, and lung tissues. This was carried out based on curated protein–protein interaction (PPI) data from protein interaction databases such as HIPPIE, human gene/protein expression databases and Gene ontology (GO) enrichment analysis using Bingo. Seven targets (MAP2K6, MATK, MAPT, PAK6, SH3GL2, CDC42EP3 and CHGB) were found to be viable objectives for LRRK2 based investigations for PD that would have minimal impact on optimal functioning within peripheral organs. Specifically, MAPT, CHGB, PAK6, and SH3GL2 interacted with LRRK2 in the brain and kidney but not in lung tissue whilst LRRK2-MAP2K6 interacted only in the cerebellum and MATK-LRRK2 interaction was absent in kidney tissues. CDC42EP3 expression levels were low in brain tissues compared to kidney/lung. The results of this computational analysis suggest new avenues for experimental investigations towards LRRK2-targeted therapeutics.
وصف الملف: text
العلاقة: https://discovery.ucl.ac.uk/id/eprint/10126612/1/Bandopadhyay_1-s2.0-S0006899321003607-main.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10126612Test/
-
8دورية أكاديمية
المؤلفون: Miki, Y, Tsushima, E, Foti, SC, Strand, KM, Asi, YT, Yamamoto, AK, Bettencourt, C, Oliveira, MCB, De Pablo-Fernández, E, Jaunmuktane, Z, Lees, AJ, Wakabayashi, K, Warner, TT, Quinn, N, Holton, JL, Ling, H
المصدر: Brain , 144 (4) pp. 1138-1151. (2021)
مصطلحات موضوعية: Parkinson’s disease, autonomic dysfunction, multiple system atrophy, progressive supranuclear palsy, red flag
الوصف: WWe studied a subset of patients with autopsy-confirmed multiple system atrophy who presented a clinical picture that closely resembled either Parkinson’s disease or progressive supranuclear palsy. These mimics are not captured by the current diagnostic criteria for multiple system atrophy. Among 218 autopsy-proven multiple system atrophy cases reviewed, 177 (81.2%) were clinically diagnosed and pathologically confirmed as multiple system atrophy (i.e. typical cases), while the remaining 41 (18.8%) had received an alternative clinical diagnosis, including Parkinson’s disease (i.e. Parkinson’s disease mimics; n = 16) and progressive supranuclear palsy (i.e. progressive supranuclear palsy mimics; n = 17). We also reviewed the clinical records of another 105 patients with pathologically confirmed Parkinson’s disease or progressive supranuclear palsy, who had received a correct final clinical diagnosis (i.e. Parkinson’s disease, n = 35; progressive supranuclear palsy-Richardson syndrome, n = 35; and progressive supranuclear palsy-parkinsonism, n = 35). We investigated 12 red flag features that would support a diagnosis of multiple system atrophy according to the current diagnostic criteria. Compared with typical multiple system atrophy, Parkinson’s disease mimics more frequently had a good levodopa response and visual hallucinations. Vertical gaze palsy and apraxia of eyelid opening were more commonly observed in progressive supranuclear palsy mimics. Multiple logistic regression analysis revealed an increased likelihood of having multiple system atrophy [Parkinson’s disease mimic versus typical Parkinson’s disease, odds ratio (OR): 8.1; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 2.3] if a patient developed any one of seven selected red flag features in the first 10 years of disease. Severe autonomic dysfunction (orthostatic hypotension and/or urinary incontinence with the need for a urinary catheter) was more frequent in clinically atypical multiple system atrophy than ...
وصف الملف: text
العلاقة: https://discovery.ucl.ac.uk/id/eprint/10126207/1/Identification%20of%20multiple%20system%20atrophy%20mimicking%20Parkinsons%20disease%20or%20progressive%20supranuclear%20palsy.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10126207Test/
-
9دورية أكاديمية
المؤلفون: Bettencourt, C, Miki, Y, Piras, IS, de Silva, R, Foti, SC, Talboom, JS, Revesz, T, Lashley, T, Balazs, R, Viré, E, Warner, TT, Huentelman, MJ, Holton, JL
المصدر: Neuropathology and Applied Neurobiology , 47 (5) pp. 640-652. (2021)
الوصف: Aims: MSA is a fatal neurodegenerative disease. Similar to Parkinson’s disease (PD), MSA is an α‐synucleinopathy, and its pathological hallmark consists of glial cytoplasmic inclusions (GCIs) containing α‐synuclein in oligodendrocytes. We previously identified consistent changes in MOBP and HIP1 DNA methylation status in MSA. We hypothesized that if differential DNA methylation at these loci is mechanistically relevant for MSA, it should have downstream consequences on gene regulation. / Methods: We investigated the relationship between MOBP and HIP1 DNA methylation and mRNA levels in cerebellar white matter from MSA and healthy controls. Additionally, we analysed protein expression using western blotting, immunohistochemistry and proximity ligation assays. / Results: We found decreased MOBP mRNA levels significantly correlated with increased DNA methylation in MSA. For HIP1, we found a distinct relationship between DNA methylation and gene expression levels in MSA compared to healthy controls, suggesting this locus may be subjected to epigenetic remodelling in MSA. Although soluble protein levels for MOBP and HIP1 in cerebellar white matter were not significantly different between MSA cases and controls, we found striking differences between MSA and other neurodegenerative diseases, including PD and Huntington’s disease. We also found that MOBP and HIP1 are mislocalized into the GCIs in MSA, where they appear to interact with α‐synuclein. / Conclusions: This study supports a role for DNA methylation in downregulation of MOBP mRNA in MSA. Most importantly, the identification of MOBP and HIP1 as new constituents of GCIs emphasizes the relevance of these two loci to the pathogenesis of MSA.
وصف الملف: text
العلاقة: https://discovery.ucl.ac.uk/id/eprint/10118287/7/de%20Silva_MOBP%20and%20HIP1%20in%20multiple%20system%20atrophy_VoR.pdfTest; https://discovery.ucl.ac.uk/id/eprint/10118287Test/
-
10رسالة جامعية
