Novel candidate blood‐based transcriptional biomarkers of machado‐joseph disease

Raposo, Mafalda; Bettencourt, Conceição; Maciel, Patrı́cia; Gao, Fuying; Ramos, Ariel Delgado; Kazachkova, Nadiya; Vasconcelos, João; Kay, Teresa; Rodrigues, Ana João; Bettencourt, Bruno Filipe; Bruges-Armas, Jácome; Geschwind, Daniel H.; Coppola, Giovanni; Lima, Manuela

doi:10.1002/mds.26238

Cited by 26 publications

(40 citation statements)

References 42 publications

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“…5a ). Of the significantly altered genes in SCA3 mouse blood, Tnfsf14 (Tumor Necrosis Factor (Ligand) Superfamily, Member 14) has previously been reported to be upregulated in blood of SCA3 patients [ 44 ]. Tnfsf14 showed a log fold change of 0.8 in SCA3 mouse blood, with a FDR of 0.048.…”

Section: Resultsmentioning

confidence: 99%

“…Sequencing of whole blood RNA revealed lower levels of Uba52 at 9 months of age, whereas 142 genes were differentially expressed at 17.5 months of age in the SCA3 mice. A total of 10 genes have been reported as transcript biomarkers in blood of SCA3 patients [ 44 ]. Of these 10 genes, only upregulation of Tumor Necrosis Factor Superfamily Member 14 ( Tnfsf14) was also observed significantly upregulated in our dataset of the SCA3 mice.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptional profiling and biomarker identification reveal tissue specific effects of expanded ataxin-3 in a spinocerebellar ataxia type 3 mouse model

Toonen

Overzier

Evers

et al. 2018

Mol Neurodegeneration

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BackgroundSpinocerebellar ataxia type 3 (SCA3) is a progressive neurodegenerative disorder caused by expansion of the polyglutamine repeat in the ataxin-3 protein. Expression of mutant ataxin-3 is known to result in transcriptional dysregulation, which can contribute to the cellular toxicity and neurodegeneration. Since the exact causative mechanisms underlying this process have not been fully elucidated, gene expression analyses in brains of transgenic SCA3 mouse models may provide useful insights.MethodsHere we characterised the MJD84.2 SCA3 mouse model expressing the mutant human ataxin-3 gene using a multi-omics approach on brain and blood. Gene expression changes in brainstem, cerebellum, striatum and cortex were used to study pathological changes in brain, while blood gene expression and metabolites/lipids levels were examined as potential biomarkers for disease.ResultsDespite normal motor performance at 17.5 months of age, transcriptional changes in brain tissue of the SCA3 mice were observed. Most transcriptional changes occurred in brainstem and striatum, whilst cerebellum and cortex were only modestly affected. The most significantly altered genes in SCA3 mouse brain were Tmc3, Zfp488, Car2, and Chdh. Based on the transcriptional changes, α-adrenergic and CREB pathways were most consistently altered for combined analysis of the four brain regions. When examining individual brain regions, axon guidance and synaptic transmission pathways were most strongly altered in striatum, whilst brainstem presented with strongest alterations in the pi-3 k cascade and cholesterol biosynthesis pathways. Similar to other neurodegenerative diseases, reduced levels of tryptophan and increased levels of ceramides, di- and triglycerides were observed in SCA3 mouse blood.ConclusionsThe observed transcriptional changes in SCA3 mouse brain reveal parallels with previous reported neuropathology in patients, but also shows brain region specific effects as well as involvement of adrenergic signalling and CREB pathway changes in SCA3. Importantly, the transcriptional changes occur prior to onset of motor- and coordination deficits.Electronic supplementary materialThe online version of this article (10.1186/s13024-018-0261-9) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Transcriptional profiling and biomarker identification reveal tissue specific effects of expanded ataxin-3 in a spinocerebellar ataxia type 3 mouse model

Toonen

Overzier

Evers

et al. 2018

Mol Neurodegeneration

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“…MJD is a late-onset polyglutamine neurodegenerative disorder caused by a mutation in the ATXN3 gene, which encodes the ubiquitously expressed protein ataxin-3 [26]. A previous study reported that TNFSF14 shows an up-regulation trend in Machado-Joseph disease (MJD) patients when compared with controls.…”

Section: Discussionmentioning

confidence: 99%

Identification of potential diagnostic biomarkers for Parkinson's disease

Feng-hua

Sun

et al. 2019

FEBS Open Bio

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The identification of biomarkers for early diagnosis of Parkinson's disease (PD) prior to the onset of symptoms may improve the effectiveness of therapy. To identify potential biomarkers, we downloaded microarray datasets of PD from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between PD and normal control (NC) groups were obtained, and the feature selection procedure and classification model were used to identify optimal diagnostic gene biomarkers for PD. A total of 1229 genes (640 up‐regulated and 589 down‐regulated) were obtained for PD, and nine DEGs (PTGDS, GPX3, SLC25A20, CACNA1D, LRRN3, POLR1D, ARHGAP26, TNFSF14 and VPS11) were selected as optimal PD biomarkers with great diagnostic value. These nine DEGs were significantly enriched in regulation of circadian sleep/wake cycle, sleep and gonadotropin‐releasing hormone signaling pathway. Finally, we examined the expression of GPX3, SLC25A20, LRRN3 and POLR1D in blood samples of patients with PD by qRT‐PCR. GPX3, LRRN3 and POLR1D exhibited the same expression pattern as in our analysis. In conclusion, this study identified nine DEGs that may serve as potential biomarkers of PD.

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“…Alterations of gene expression were also detected in peripheral blood samples from MJD/SCA3 patients when compared to controls, providing valuable clues for the development of potential biomarkers (Raposo et al . ). The alteration of mRNA expression patterns of several genes associated with neuronal functions was reported in a MJD/SCA3 transgenic mouse model expressing ataxin‐3 MJD1a isoform with 79 glutamines (Chou et al .…”

Section: Therapeutic Perspectivesmentioning

confidence: 97%

Machado–Joseph disease/spinocerebellar ataxia type 3: lessons from disease pathogenesis and clues into therapy

Matos

Almeida

Nóbrega

2018

Journal of Neurochemistry

103

127

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Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an incurable disorder, widely regarded as the most common form of spinocerebellar ataxia in the world. MJD/SCA3 arises from mutation of the ATXN3 gene, but this simple monogenic cause contrasts with the complexity of the pathogenic mechanisms that are currently admitted to underlie neuronal dysfunction and death. The aberrantly expanded protein product - ataxin-3 - is known to aggregate and generate toxic species that disrupt several cell systems, including autophagy, proteostasis, transcription, mitochondrial function and signalling. Over the years, research into putative therapeutic approaches has often been devoted to the development of strategies that counteract disease at different stages of cellular pathogenesis. Silencing the pathogenic protein, blocking aggregation, inhibiting toxic proteolytic processing and counteracting dysfunctions of the cellular systems affected have yielded promising ameliorating results in studies with cellular and animal models. The current review analyses the available studies dedicated to the investigation of MJD/SCA3 pathogenesis and the exploration of possible therapeutic strategies, focusing primarily on gene therapy and pharmacological approaches rooted on the molecular and cellular mechanisms of disease.

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Novel candidate blood‐based transcriptional biomarkers of machado‐joseph disease

Cited by 26 publications

References 42 publications

Transcriptional profiling and biomarker identification reveal tissue specific effects of expanded ataxin-3 in a spinocerebellar ataxia type 3 mouse model

Transcriptional profiling and biomarker identification reveal tissue specific effects of expanded ataxin-3 in a spinocerebellar ataxia type 3 mouse model

Identification of potential diagnostic biomarkers for Parkinson's disease

Machado–Joseph disease/spinocerebellar ataxia type 3: lessons from disease pathogenesis and clues into therapy

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