Altered infective competence of the human gut microbiome in COVID-19

in Microbiome (2023), 11(1), 46

BACKGROUND: Infections with SARS-CoV-2 have a pronounced impact on the gastrointestinal tract and its resident microbiome. Clear differences between severe cases of infection and healthy individuals have ... [more ▼]

BACKGROUND: Infections with SARS-CoV-2 have a pronounced impact on the gastrointestinal tract and its resident microbiome. Clear differences between severe cases of infection and healthy individuals have been reported, including the loss of commensal taxa. We aimed to understand if microbiome alterations including functional shifts are unique to severe cases or a common effect of COVID-19. We used high-resolution systematic multi-omic analyses to profile the gut microbiome in asymptomatic-to-moderate COVID-19 individuals compared to a control group. RESULTS: We found a striking increase in the overall abundance and expression of both virulence factors and antimicrobial resistance genes in COVID-19. Importantly, these genes are encoded and expressed by commensal taxa from families such as Acidaminococcaceae and Erysipelatoclostridiaceae, which we found to be enriched in COVID-19-positive individuals. We also found an enrichment in the expression of a betaherpesvirus and rotavirus C genes in COVID-19-positive individuals compared to healthy controls. CONCLUSIONS: Our analyses identified an altered and increased infective competence of the gut microbiome in COVID-19 patients. Video Abstract. [less ▲]

Generation of two induced pluripotent stem cell lines and the corresponding isogenic controls from Parkinson's disease patients carrying the heterozygous mutations c.1290A > G (p.T351A) or c.2067A > G (p.T610A) in the RHOT1 gene encoding Miro1.

in Stem cell research (2023), 69

Primary skin fibroblasts from two Parkinson's disease (PD) patients carrying distinct heterozygous mutations in the RHOT1 gene encoding Miro1, namely c.1290A > G (Miro1 p.T351A) and c.2067A > G (Miro1 p ... [more ▼]

Primary skin fibroblasts from two Parkinson's disease (PD) patients carrying distinct heterozygous mutations in the RHOT1 gene encoding Miro1, namely c.1290A > G (Miro1 p.T351A) and c.2067A > G (Miro1 p.T610A), were converted into induced pluripotent stem cells (iPSCs) by episomal reprogramming. The corresponding isogenic gene-corrected lines have been generated using CRISPR/Cas9 technology. Here, we provide a comprehensive characterization and quality assurance of both isogenic pairs, which will be used to study Miro1-related molecular mechanisms underlying neurodegeneration in iPSC-derived neuronal models (e.g., midbrain dopaminergic neurons and astrocytes). [less ▲]

SMASCH: Facilitating multi-appointment scheduling in longitudinal clinical research studies and care programs

Poster (2022, September 20)

Longitudinal clinical research studies require conducting various assessments over long periods of time. Such assessments comprise numerous stages, requiring different resources defined by ... [more ▼]

Longitudinal clinical research studies require conducting various assessments over long periods of time. Such assessments comprise numerous stages, requiring different resources defined by multidisciplinary research staff and aligned with available infrastructure and equipment, altogether constrained by time. While it is possible to manage the allocation of resources manually, it is complex and error-prone. Efficient multi-appointment scheduling is essential to assist clinical teams, ensuring high participant retention and producing successful clinical studies, directly impacting patient throughput and satisfaction. We present Smart Scheduling (SMASCH) system [1], a web application for multi-appointment scheduling management aiming to reduce times, optimise resources and secure personal identifiable information. SMASCH facilitates clinical research and integrated care programs in Luxembourg, providing features to better manage multi-appointment scheduling problems (MASPs) characteristic of longitudinal clinical research studies and speed up management tasks. It is present in multiple clinical research and integrated care programs in Luxembourg since 2017, including Dementia Prevention Program, the study for Mild Cognitive Impairment and gut microbiome, and the National Centre of Excellence in Research on Parkinson’s disease [2] which encompasses the study for REM sleep behaviour disorder and the Luxembourg Parkinson’s Study. SMASCH is a free and open-source solution available both as a Linux package and Docker image. [less ▲]

Genetic stratification of motor and QoL outcomes in Parkinson's disease in the EARLYSTIM study

in Parkinsonism and Related Disorders (2022)

Purpose The decision for subthalamic deep brain stimulation (STN-DBS) in Parkinson's disease (PD) relies on clinical predictors. Whether genetic variables could predict favourable or unfavourable ... [more ▼]

Purpose The decision for subthalamic deep brain stimulation (STN-DBS) in Parkinson's disease (PD) relies on clinical predictors. Whether genetic variables could predict favourable or unfavourable decisions is under investigation. Objective First, we aimed to reproduce the previous observation that SNCA rs356220 was associated with favourable STN-DBS motor response. In additional exploratory analyses, we studied if other PD risk and progression variants from the latest GWAS are associated with therapeutic outcome. Further, we evaluated the predictive value of polygenic risk scores. Methods We comprehensively genotyped patients from the EarlyStim cohort using NeuroChip, and assessed the clinico-genetic associations with longitudinal outcome parameters. Results The SNCA rs356220 variant did not predict UPDRS III outcomes. However, it was associated with quality of life improvement in secondary analyses. Several polymorphisms from previously identified GWAS hits predicted motor or quality of life outcomes in DBS patients. Polygenic risk scores did not predict any outcome parameter. Conclusions Our findings support the hypothesis that different common genetic markers are associated with favourable quality of life outcomes of STN-DBS in PD. These findings can be the basis for further validation in larger and independent cohorts. [less ▲]

Evaluation of SORL1 in Lewy Body Dementia Identifies No Significant Associations

in Movement Disorders (2022)

Lewy body dementia (LBD) is a clinically heterogeneous neurodegenerative disorder characterized by parkinsonism, visual hallucinations, fluctuating mental status, and rapid eye movement sleep behavior ... [more ▼]

Lewy body dementia (LBD) is a clinically heterogeneous neurodegenerative disorder characterized by parkinsonism, visual hallucinations, fluctuating mental status, and rapid eye movement sleep behavior disorder. LBD lies along a spectrum between Parkinson's disease and Alzheimer's disease, and recent evidence suggests that the genetic architectures of these age-related syndromes are intersecting. In summary, we did not find a significant enrichment of rare, damaging SORL1 mutations in our well-powered LBD cohort. Our data set is, to our knowledge, the largest genome-sequence cohort in this understudied disease. Although it is possible that an association was missed due to allelic heterogeneity, our findings indicate that caution should be exercised when interpreting SORL1 mutations in LBD, as the current evidence does not conclusively support an association with disease risk. [less ▲]

Early-to-mid idiopathic Parkinson’s disease shows a more cytotoxic but declined CD8-regulatory peripheral immune profile

E-print/Working paper (2022)

Parkinson’s disease (PD) is the second most common neurodegenerative disease. Brain neuroinflammation plays a role in PD pathogenesis. However, the involvement of the peripheral immune system has not been ... [more ▼]

Parkinson’s disease (PD) is the second most common neurodegenerative disease. Brain neuroinflammation plays a role in PD pathogenesis. However, the involvement of the peripheral immune system has not been systematically investigated. Here we analyzed >700 combinatorial immunological features in fresh blood of 28 early-to-mid-stage PD patients and 24 matched controls. We found an enhanced cytotoxic immune profile in idiopathic PD patients (iPD), with a higher frequency of terminally-differentiated effector CD8 T (TEMRA), late-differentiated CD8+ natural killer T cells and neutrophils. This immune profile was intensified by elevated serum granzyme A, reduced percentages of CD8+FOXP3+ regulatory T cells and group 2 innate lymphoid cells with immunosuppressive or tolerance-inducing functions. The frequency of CD8 TEMRA was negatively correlated with disease duration, suggesting a contribution to PD pathogenesis. Our work provides a comprehensive map on disturbed peripheral adaptive and innate immune cells in early-to-mid iPD, proposing easily-accessible candidates for early diagnosis and treatments. [less ▲]

The Interaction between HLA-DRB1 and Smoking in Parkinson's Disease Revisited

in Movement Disorders (2022)

Abstract Background Two studies that examined the interaction between HLA-DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions. Objective To perform a large-scale ... [more ▼]

Abstract Background Two studies that examined the interaction between HLA-DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions. Objective To perform a large-scale independent replication of the HLA-DRB1 × smoking interaction. Methods We genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA-DRB1. Results At the amino acid level, a valine at position 11 (V11) in HLA-DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95 confidence interval, 0.59–0.93, PInteraction = 0.028). In silico predictions of the influence of V11 and smoking-induced modifications of α-synuclein on binding affinity showed findings consistent with this interaction pattern. Conclusions Despite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [less ▲]

PARK7/DJ-1 promotes pyruvate dehydrogenase activity and maintains T(reg) homeostasis during ageing.

in Nature metabolism (2022), 4(5), 589-607

Pyruvate dehydrogenase (PDH) is the gatekeeper enzyme of the tricarboxylic acid (TCA) cycle. Here we show that the deglycase DJ-1 (encoded by PARK7, a key familial Parkinson's disease gene) is a pacemaker ... [more ▼]

Pyruvate dehydrogenase (PDH) is the gatekeeper enzyme of the tricarboxylic acid (TCA) cycle. Here we show that the deglycase DJ-1 (encoded by PARK7, a key familial Parkinson's disease gene) is a pacemaker regulating PDH activity in CD4(+) regulatory T cells (T(reg) cells). DJ-1 binds to PDHE1-β (PDHB), inhibiting phosphorylation of PDHE1-α (PDHA), thus promoting PDH activity and oxidative phosphorylation (OXPHOS). Park7 (Dj-1) deletion impairs T(reg) survival starting in young mice and reduces T(reg) homeostatic proliferation and cellularity only in aged mice. This leads to increased severity in aged mice during the remission of experimental autoimmune encephalomyelitis (EAE). Dj-1 deletion also compromises differentiation of inducible T(reg) cells especially in aged mice, and the impairment occurs via regulation of PDHB. These findings provide unforeseen insight into the complicated regulatory machinery of the PDH complex. As T(reg) homeostasis is dysregulated in many complex diseases, the DJ-1-PDHB axis represents a potential target to maintain or re-establish T(reg) homeostasis. [less ▲]

Polygenic Resilience Modulates the Penetrance of Parkinson Disease Genetic Risk Factors

in Annals of Neurology (2022)

Objective: The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of ... [more ▼]

Objective: The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual-level genetic data available. Methods: We calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership–Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome-wide association study meta-analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene-based analyses and functional enrichment analyses. Results: A higher polygenic resilience score was associated with a lower risk for PD (β = −0.054, standard error [SE] = 0.022, p = 0.013). Although no single locus reached genome-wide significance, MAGMA gene-based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow-sense heritability associated with resilience to PD (h2 = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci. Interpretation: The present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high-risk genetic burden from developing PD. ANN NEUROL 2022 [less ▲]

Retrograde Procedural Memory in Parkinson’s Disease: A Cross-Sectional, Case-Control Study

in Journal of Parkinson's Disease (2022)

Background: The analysis of the procedural memory is particularly relevant in neurodegenerative disorders like Parkinson’s disease, due to the central role of the basal ganglia in procedural memory. It ... [more ▼]

Background: The analysis of the procedural memory is particularly relevant in neurodegenerative disorders like Parkinson’s disease, due to the central role of the basal ganglia in procedural memory. It has been shown that anterograde procedural memory, the ability to learn a new skill, is impaired in Parkinson’s disease. However, retrograde procedural memory, the long-term retention and execution of skills learned in earlier life stages, has not yet been systematically investigated in Parkinson’s disease. Objective: This study aims to investigate retrograde procedural memory in people with Parkinson’s disease.We hypothesized that retrograde procedural memory is impaired in people with Parkinson’s disease compared to an age- and gender-matched control group. Methods: First, we developed the CUPRO evaluation system, an extended evaluation system based on the Cube Copying Test, to distinguish the cube copying procedure, representing functioning of retrograde procedural memory, and the final result, representing the visuo-constructive abilities. Development of the evaluation system included tests of discriminant validity. Results: Comparing people with typical Parkinson’s disease (n = 201) with age- and gender-matched control subjects (n = 201), we identified cube copying performance to be significantly impaired in people with Parkinson’s disease (p = 0.008) No significant correlation was observed between retrograde procedural memory and disease duration. Conclusion: We demonstrated lower cube copying performance in people with Parkinson’s disease compared to control subjects, which suggests an impaired functioning of retrograde procedural memory in Parkinson’s disease. [less ▲]