👤 Georg Halder

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

In recent years, brain-derived neurotrophic factor (BDNF) and matrix metalloproteinase-9 (MMP-9) have garnered interest for their involvement in epilepsy. This study evaluated the serum levels of BDNF and MMP-9 in pediatric patients with epilepsy compared to healthy controls and assessed the effect of valproate on serum BDNF and MMP-9. Children aged 1 year to 12 years, diagnosed with epilepsy (n=30), and age-matched healthy controls (n=30) were included. All participants were followed up for 16 weeks and assessed for changes in serum BDNF and MMP-9 levels. Children with epilepsy had significantly lower BDNF and higher MMP-9 levels compared to healthy controls at baseline. Following 16 weeks of treatment with valproate, BDNF levels were increased significantly ( The findings suggest the involvement of BDNF and MMP-9 in the pathogenesis of epilepsy. Serum BDNF and MMP-9 levels were increased and decreased, respectively, following valproate treatment in children with epilepsy. Hence, BDNF and MMP-9 could be potential biomarkers in pediatric epilepsy. Large sample sizes and long-term studies are warranted to confirm the findings. Show less

The juvenile form of neuronal ceroid Lipofuscinosis (JNCL) is the most common form within this group of rare lysosomal storage disorders, causing pediatric neurodegeneration. The genetic disorder, which is caused by recessive mutations affecting the CLN3 gene, features progressive vision loss, cognitive and motor decline and other psychiatric conditions, seizure episodes, leading to premature death. Animal models have traditionally aid the understanding of the disease mechanisms and pathology and are very relevant for biomarker research and therapeutic testing. Nevertheless, there is a need for establishing reliable and predictive human cellular models to study the disease. Since patient material, particularly from children, is scarce and difficult to obtain, we generated an engineered a CLN3-mutant isogenic human induced pluripotent stem cell (hiPSC) line carrying the c.1054C → T pathologic variant, using state of the art CRISPR/Cas9 technology. To prove the suitability of the isogenic pair to model JNCL, we screened for disease-specific phenotypes in non-neuronal two-dimensional cell culture models as well as in cerebral brain organoids. Our data demonstrates that the sole introduction of the pathogenic variant gives rise to classical hallmarks of JNCL in vitro. Additionally, we discovered an alteration of the splicing caused by this particular mutation. Next, we derived cerebral organoids and used them as a neurodevelopmental model to study the particular effects of the CLN3 Show less

The Hippo tumor-suppressor pathway controls tissue growth in Drosophila and mammals by regulating cell proliferation and apoptosis. The Hippo pathway includes the Fat cadherin, a transmembrane protein, which acts upstream of several other components that form a kinase cascade that culminates in the regulation of gene expression through the transcriptional coactivator Yorkie (Yki). Our previous work in Drosophila indicated that Merlin (Mer) and Expanded (Ex) are members of the Hippo pathway and act upstream of the Hippo kinase. In contrast to this model, it was suggested that Mer and Ex primarily regulate membrane dynamics and receptor trafficking, thereby affecting Hippo pathway activity only indirectly. Here, we examined the effects of Mer, Ex and the Hippo pathway on the size of the apical membrane and on apical-basal polarity complexes. We found that mer;ex double mutant imaginal disc cells have significantly increased levels of apical membrane determinants, such as Crb, aPKC and Patj. These phenotypes were shared with mutations in other Hippo pathway components and required Yki, indicating that Mer and Ex signal through the Hippo pathway. Interestingly, however, whereas Crb was required for the accumulation of other apical proteins and for the expansion of the apical domain observed in Hippo pathway mutants, its elimination did not significantly reverse the overgrowth phenotype of warts mutant cells. Therefore, Hippo signaling regulates cell polarity complexes in addition to and independently of its growth control function in imaginal disc cells. Show less