👤 Brit Mollenhauer

Alterations in the gut microbiome and a "leaky" gut are associated with Parkinson's disease (PD), which implies the prospect of rebalancing via dietary intervention. Here, we investigate the impact of a diet rich in resistant starch on the gut microbiome through a multi-omics approach. We conducted a randomized, controlled trial with short-term and long-term phases involving 74 PD patients of three groups: conventional diet, supplementation with resistant starch, and high-fibre diet. Our findings reveal associations between dietary patterns and changes in the gut microbiome's taxonomic composition, functional potential, metabolic activity, and host inflammatory proteome response. Resistant starch supplementation led to an increase in Faecalibacterium species and short-chain fatty acids alongside a reduction in opportunistic pathogens. Long-term supplementation also increased blood APOA4 and HSPA5 and reduced symptoms of PD. Our study highlights the potential of dietary interventions to modulate the gut microbiome and improve the quality of life for PD patients. Show less

Abdominal aortic aneurysms (AAAs) are characterized by ECM (extracellular matrix) degradation and chronic vascular inflammation, with macrophages playing a key role. The mechanisms regulating macrophage activation in AAA remain incompletely understood. Vascular macrophages express Olfr2 (olfactory receptor 2), a GPCR (G-protein-coupled receptor) implicated in inflammation, but its role in AAA development is unknown. We investigated the role of Olfr2 in AAA using PPE (porcine pancreatic elastase) infusion in Olfr2-deficient ( Microarray analysis revealed increased expression of the human Olfr2 regulates monocyte recruitment and macrophage-driven inflammation during AAA. Its genetic deletion or pharmacological inhibition protects against AAA, whereas receptor activation worsens the disease. Olfr2 represents a critical modulator of vascular inflammation and a potential therapeutic target in AAA. Show less

There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD). To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD. Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests. We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls. Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society. Show less

Impaired lysosomal degradation of α-synuclein and other cellular constituents may play an important role in Parkinson's disease (PD). Rare genetic variants in the glucocerebrosidase (GBA) gene were consistently associated with PD. Here we examine the association between rare variants in lysosomal candidate genes and PD. We investigated the association between PD and rare genetic variants in 23 lysosomal candidate genes in 4096 patients with PD and an equal number of controls using pooled targeted next-generation DNA sequencing. Genewise association of rare variants in cases or controls was analyzed using the optimized sequence kernel association test with Bonferroni correction for the 23 tested genes. We confirm the association of rare variants in GBA with PD and report novel associations for rare variants in ATP13A2, LAMP1, TMEM175, and VPS13C. Rare variants in selected lysosomal genes, first and foremost GBA, are associated with PD. Rare variants in ATP13A2 and VPC13C previously linked to monogenic PD and more common variants in TMEM175 and VPS13C previously linked to sporadic PD in genome-wide association studies are associated with PD. © 2020 International Parkinson and Movement Disorder Society. Show less

Parkinson's disease (PD) is a genetically heterogeneous disorder and new putative disease genes are discovered constantly. Therefore, whole-exome sequencing could be an efficient approach to genetic testing in PD. To evaluate its performance in early-onset sporadic PD, we performed diagnostic exome sequencing in 80 individuals with manifestation of PD symptoms at age 40 or earlier and a negative family history of PD. Variants in validated and candidate disease genes and risk factors for PD and atypical Parkinson syndromes were annotated, followed by further analysis for selected variants. We detected pathogenic variants in Mendelian genes in 6.25% of cases and high-impact risk factor variants in GBA in 5% of cases, resulting in overall maximum diagnostic yield of 11.25%. One individual was compound heterozygous for variants affecting canonical splice sites in VPS13C, confirming the causal role of protein-truncating variants in this gene linked to autosomal-recessive early-onset PD. Despite the low diagnostic yield of exome sequencing in sporadic early-onset PD, the confirmation of the recently discovered VPS13C gene highlights its advantage over using predefined gene panels. Show less

Next-generation sequencing has dramatically increased genome-wide profiling options and conceptually initiates the possibility for personalized cancer therapy. State-of-the-art sequencing studies yield large candidate gene sets comprising dozens or hundreds of mutated genes. However, few technologies are available for the systematic downstream evaluation of these results to identify novel starting points of future cancer therapies.We improved and extended a site-specific recombination-based system for systematic analysis of the individual functions of a large number of candidate genes. This was facilitated by a novel system for the construction of isogenic constitutive and inducible gain- and loss-of-function cell lines. Additionally, we demonstrate the construction of isogenic cell lines with combinations of the traits for advanced functional in vitro analyses. In a proof-of-concept experiment, a library of 108 isogenic melanoma cell lines was constructed and 8 genes were identified that significantly reduced viability in a discovery screen and in an independent validation screen. Here, we demonstrate the broad applicability of this recombination-based method and we proved its potential to identify new drug targets via the identification of the tumor suppressor DUSP6 as potential synthetic lethal target in melanoma cell lines with BRAF V600E mutations and high DUSP6 expression. Show less