Biology subjects

Vasconcelos, J.

Publications and source records attributed to Vasconcelos, J..

6 recordsLinked to original sources

bioRxiv2023

Blood DDIT4 and TRIM13 transcript levels mark the early stages of Machado-Joseph disease

Machado-Joseph disease (MJD) is a rare late-onset polyglutamine neurodegenerative disease caused by the expansion of a CAG repeat in the ATXN3 gene encoding the ataxin- 3 (ATXN3) protein. Several studies have identified changes in the abundance of select transcripts and proteins in blood samples of MJD mutation carriers. Here, we aimed to: 1) identify blood transcriptional changes that could be potential biomarkers of MJD from preclinical to symptomatic disease stages; 2) correlate levels of differentially expressed transcripts in blood of MJD carriers with demographic, genetics, and clinical features; and 3) evaluate whether the identified differential abundance of selected transcripts in blood of MJD subjects is preserved in post-mortem brains of MJD patients. Using real- time quantitative PCR, we observed consistent dysregulation of DDIT4, TRIM13 and P2RY13 transcript levels in blood samples of MJD subjects from different disease stages (from preclinical to symptomatic), and of patients from two cohorts with different backgrounds (Azores and Brazil). Importantly, combined blood DDIT4 and TRIM13 transcript levels display a very high accuracy to discriminate MJD carriers in preclinical stage, early-stage patients, and patients with more than five years of disease duration from respective controls (AUC=1.00, AUC=0.96, and AUC=0.90, respectively). Moreover, in the combined group of Azorean and Brazilian patients, blood levels of P2RY13 transcript correlate with age at onset, and abundance of DDIT4 and TRIM13 transcripts correlate with the CAG repeat size of the expanded ATXN3 allele. In the subgroup of early-stage Azorean patients, blood levels of TRIM13 transcripts correlate with age at disease onset. Interestingly, abundance of DDIT4, TRIM13 and P2RY13 proteins is also altered in brains of MJD patients. In summary, this work shows that blood DDIT4 and TRIM13 transcript levels are potentially blood-based biomarkers of MJD of special usefulness in marking preclinical and early stages of the disease, and points for common dysregulated processes involving DDIT4, TRIM13 and P2RY13 in the blood and the brain of MJD subjects.

neuroscience↗

bioRxiv2023

Blood and cerebellar abundance of ATXN3 splice variants in spinocerebellar ataxia type 3/Machado-Joseph disease

BackgroundSpinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is an autosomal dominant polyglutamine disease. SCA3/MJD causative gene, ATXN3, is known to undergo alternative splicing (AS) and 54 transcripts are currently annotated. Differences in the toxicity of ataxin-3 protein isoforms, harbouring on its C-terminus two or three ubiquitin interacting motifs (UIMs), were previously uncovered, raising the hypothesis that specific ATXN3 splice variants play key roles in promoting the selective toxicity displayed in SCA3/MJD. MethodsUsing RNA-seq datasets we identified and determined the abundance of annotated ATXN3 transcripts in blood (n=60) and cerebellum (n=12) of SCA3/MJD subjects and controls. ResultsGlobally, the number and the abundance of individual ATXN3 transcripts were higher in the cerebellum than in the blood. While the most abundant transcript in the cerebellum was a protein with a coding sequence not defined of unknown function (ATXN3-208), the transcript with the highest abundance in blood was the reference transcript (ATXN3-251) which translates into an ataxin-3 isoform harboring three UIMs. Noteworthy, the abundance of ATXN3-251 and ATXN3-214, two out of the four transcripts that encode full-length ataxin-3 protein isoforms but differ in the C-terminus were strongly related with tissue expression specificity: ATXN3-251 (3UIM) was expressed in blood 50-fold more than in cerebellum, whereas ATXN3-214 (2UIM) was expressed in the cerebellum 20-fold more than in blood. ConclusionsThese findings provide new insights into the elucidation of ATXN3 AS in different tissues, contributing for a better understanding of SCA3/MJD pathogenesis and providing information for the development of future effective ATXN3 mRNA-lowering therapies.

genetics↗

bioRxiv2023

Tissue-specific vulnerability to apoptosis in Machado-Joseph disease

Machado-Joseph disease (MJD) is a dominant neurodegenerative disease caused by an expanded CAG repeat in the ATXN3 gene encoding the ataxin-3 protein. Several cellular processes, including transcription and apoptosis, are disrupted in MJD. To gain further insights into the extent of dysregulation of mitochondrial apoptosis in MJD, and to evaluate if expression alterations of specific apoptosis genes/proteins could be used as transcriptional biomarkers of disease, the levels of BCL2, BAX and TP53 and the BCL2/BAX ratio, an indicator of susceptibility to apoptosis, were assessed in blood and post-mortem brain samples from MJD subjects and MJD transgenic mice and controls. While patients show reduced levels of blood BCL2 transcripts, this measurement displays low accuracy to discriminate patients from matched controls. However, increased levels of blood BAX transcripts and decreased BCL2/BAX ratio are associated with earlier onset, indicating a possible association with MJD pathogenesis. Post-mortem MJD brains show increased BCL2/BAX transcript ratio in the dentate cerebellar nucleus (DCN) and increased BCL2/BAX insoluble protein ratio in the DCN and pons, suggesting that in these regions, severely affected by degeneration in MJD, cells show signs of apoptosis resistance. Interestingly, a follow-up study of 18 patients further shows that blood BCL2 and TP53 transcript levels increase over time in MJD patients. Furthermore, while the similar levels of blood BCL2, BAX, and TP53 transcripts observed in preclinical subjects and controls is mimicked by pre-symptomatic MJD mice, the expression profile of these genes in patient brains is partially replicated by symptomatic MJD mice. Globally, our findings indicate that there is tissue-specific vulnerability to apoptosis in MJD subjects and that this tissue dependent behavior is partially replicated in a MJD mouse model.

neuroscience↗

bioRxiv2022

The impact of the ABO/Rh blood group on susceptibility and severity among COVID-19 patients in Luanda, Angola

SARS-CoV-2 is a public health concern worldwide. Identification of biological factors that could influence transmission and worsen the disease has been the subject of extensive investigation. Herein, we investigate the impact of the ABO/Rh blood group on susceptibility and severity among COVID-19 patients in Luanda, Angola. This was a multicentric cohort study conducted with 101 COVID-19 patients. Chi-square and logistic regression were calculated to check factors related to the worsening of the disease and deemed significant when p<0.05. Blood type O (51.5%) and Rh-positive (93.1%) were the most frequent. Patients from blood type O had a high risk to severe disease [OR: 1.33 (95% CI: 0.42 - 4.18), p=0.630] and hospitalization [OR: 2.59 (95% CI: 0.84 - 8.00), p=0.099]. Also, Rh-positive blood type presented a high risk for severe disease (OR: 10.6, p=0.007) and hospitalization (OR: 6.04, p=0.026). We find a high susceptibility, severity, hospitalization, and mortality, respectively, among blood group O and Rh-positive patients, while blood group AB presented a low susceptibility, severity, hospitalization, and mortality, respectively. Our findings add to the body of evidence suggesting that ABO/Rh blood groups play an important role in the course of SARS-CoV-2 infection.

genetics↗

bioRxiv2019

Genome-wide association study identifies genetic factors that modify age at onset in Machado-Joseph disease

Machado-Joseph disease (MJD/SCA3) is the most common form of dominantly inherited ataxia worldwide. The disorder is caused by an expanded CAG repeat in the ATXN3 gene. Past studies have revealed that the length of the expansion partly explains the disease age at onset (AO) variability of MJD, which is confirmed in this study. Using a total of 786 MJD patients from five different geographical origins, a genome-wide association study (GWAS) was conducted to identify additional AO modifying factors that could explain some of the residual AO variability. We identified nine suggestively associated loci (P < 1 x 10-5). These loci were enriched for genes involved in vesicle transport, olfactory signaling, and synaptic pathways. Furthermore, associations between AO and the TRIM29 and RAG genes suggests that DNA repair mechanisms might be implicated in MJD pathogenesis. Our study demonstrates the existence of several additional genetic factors, along with CAG expansion, that may lead to a better understanding of the genotype-phenotype correlation in MJD.

genetics↗

bioRxiv2019

Emergence of the Zika virus Asian lineage in Angola

Research In ContextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed without language restrictions using the keywords Zika and Africa for papers published to October 2018. We also checked available Situation Report publications from WHO for evidence of Zika virus (ZIKV) or congenital Zika disease in Africa. ZIKV African lineage has been detected within Africa since the mid 20th century, yet evidence for spread of the ZIKV Asian lineage within Africa is limited. Two countries in Africa (Cabo Verde and Angola) have reported ZIKV cases that are believed to be caused by a newly introduced Asian lineage virus. Sequence data are critical for confirming and understanding the spread of ZIKV Asian lineage within Africa, but these data are currently limited to a single 193bp fragment of the ZIKV NS1 gene from Angola. In addition, whilst epidemiological data on ZIKV and suspected microcephaly cases have been reported in detail from Cabo Verde, data from Angola are extremely limited.\n\nAdded value of this studyWe provide a detailed report of detected ZIKV acute cases and suspected microcephaly cases in Angola. We sequence ZIKV genomes from three acutely infected cases. These represent the first three Asian lineage genomes available from Africa, one of which was acquired from a baby with confirmed microcephaly. Analysis of these sequences suggests that ZIKV may have been introduced to Angola between July 2015 and June 2016, after which it likely circulated for at least one year. This provides the first genetic confirmation of autochthonous ZIKV Asian lineage transmission within Africa. We suggest that the virus was more likely introduced to Angola directly from Brazil, rather than from Cabo Verde. Our analyses from Angola, only the second African country to report presence of the Asian virus lineage, therefore improve our understanding of the extent and clinical impact of ZIKV Asian lineage in the continent.\n\nImplications of all the available evidenceThe circulation of ZIKV Asian lineage within parts of sub-Saharan Africa is concerning given the potential for continued viral spread across much of the continent. Available evidence suggests that ZIKV has circulated and caused cases of microcephaly in Cabo Verde and in Angola. Detecting additional ZIKV transmission using only clinical data on suspected microcephaly or clusters of mild illness may be challenging in countries where systems for reporting birth defects are limited and infectious disease burden is high. Further spread of the ZIKV Asian lineage would likely not be detected unless molecular surveillance systems for ZIKV are implemented to routinely monitor ZIKV transmission in Africa. Implementation of such a surveillance system is especially important in countries that are linked by high human mobility to areas that have experienced recent or ongoing outbreaks of ZIKV.\n\nAbstractO_ST_ABSBackgroundC_ST_ABSZika virus (ZIKV) infections and suspected microcephaly cases have been recently reported in Angola, but no data are available on the origins, epidemiology, and diversity of the virus.\n\nMethodsSerum samples from 54 suspected ZIKV cases, 76 suspected microcephaly cases, and 24 mothers of infants with suspected microcephaly were received by the Angolan Ministry of Health. Computed tomographic brain imaging and serological assays (PRNT) were conducted on one microcephalic infant. All sera were tested for ZIKV by RT-qPCR. 349 samples from HIV+ patients and 336 samples from patients suspected of chikungunya virus or dengue virus infection were also tested. Portable sequencing was used to generate Angolan ZIKV genome sequences, including from a ZIKV+ neonate with microcephaly born in Portugal to an Angolan resident. Genetic and mobility data were analysed to investigate the date of introduction and geographic origin of ZIKV in Angola.\n\nFindingsFour autochthonous cases were ZIKV positive via RT-qPCR, with all positive samples collected between December 2016 and June 2017. Viral genomes were generated for two of these cases, and from the neonate with microcephaly identified in Portugal. Genetic analyses and other data indicate that ZIKV was introduced to Angola from Brazil between July 2015 and June 2016. This introduction likely initiated local ZIKV circulation in Angola that continued until June 2017. The scanned microcephaly case showed brain abnormalities consistent with congenital Zika syndrome and serological evidence for maternal ZIKV infection.\n\nInterpretationOur analyses confirm the autochthonous transmission of the ZIKV Asian lineage in continental Africa. Conducting ZIKV surveillance throughout Africa is critical in the light of presented evidence for autochthonous ZIKV transmission in Angola, and associated microcephaly cases.\n\nFundingRoyal Society, Wellcome Trust, CNPq, CAPES, ERC, Oxford Martin School, Global Challenges Research Fund, Africa Oxford, and John Fell Fund.

epidemiology↗