Project description:Deficiency of pnkp in zebrafish causes microcephaly, seizures and developmental delay through mitochondrial dysfunction (PRJCA048440)
Project description:Mitochondrial dysfunction, disruption of F-actin polymerization, and transcriptomic alterations in zebrafish larvae exposed to trichloroethylene
Project description:The pesticide fipronil affects transcriptional networks related to mitochondrial dysfunction and methylation in zebrafish embryos (Danio rerio)
Project description:In mammals, retinal damage is followed by Müller glia cell activation and proliferation. While retinal gliosis persists in adult mammals after an insult or disease, some vertebrates, including zebrafish, have the capacity to regenerate. We believe we are the first group to show that gliosis is a fibrotic-like process in mammals’ eyes caused by differential activation of canonical and non-canonical TGFβ signaling pathways.
Project description:Protein misfolding and aggregation deregulate the proteostasis network and are hallmarks of cell degeneration processes associated with aging and human diseases. But how proteome aggregation causes cell degeneration remains controversial due to the lack of suitable methods for controlling proteome aggregation at the cellular and organismal levels. To overcome this limitation, we have generated zebrafish embryos that exhibit protein aggregation due to misincorporation of Serine (Ser) at non-cognate protein sites on a proteome wide scale. These mistranslating embryos display up regulation of the unfolded protein response (UPR) and the ubiquitin proteasome pathway (UPP), increased protein ubiquitination and down-regulation of protein biosynthesis. Proteome damage also induces major disruption of the mitochondrial network, accompanied by mitochondrial and nuclear DNA damage and accumulation of reactive oxygen species (ROS). Taken together, our data highlight important roles of gene translational accuracy in the maintenance of ER homeostasis, DNA damage, mitochondrial function and oxidative stress. We postulate that protein biosynthesis errors (PBE) contribute to proteome aggregation and are a main cause of mitochondrial disruption.
Project description:Metabolites produced by human gut microbiome have a profound influence on brain health with increasing associations to Parkinson’s disease pathology that lack a mechanistic insight. Using Caenorhabditis elegans model expressing human α-synuclein, we systematically tested key microbial fermentation products and identified succinate as a potent driver of pathology. As succinate administration was found to alter major PD associated pathological end-points, we further investigated the changes at transcriptional level by performing the whole worm transcriptome profiling of the wild-type strain. Through differentially expressed genes (DEGs), we examined the extent of physiological impact exerted by an exogenously administered metabolite and tried to comprehend the mechanism through which succinate generates a proteotoxic environment that promotes aggregation of alpha-synuclein in a transgenic C. elegans strain expressing human alpha-synuclein. It also helped us to identify the molecular pathways that result in mitochondrial dysfunction and substantiate our findings.
Project description:A loss of the checkpoint kinase ATM leads to impairments in the DNA damage response, and in humans causes cerebellar neurodegeneration, and a high risk to cancer. A loss of ATM is also associated with increased protein aggregation. The relevance and characteristics of this aggregation are still incompletely understood. Moreover, it is unclear to what extent other genotoxic conditions can trigger protein aggregation as well. Here, we show that targeting ATM, but also ATR or DNA topoisomerases result in a similar, widespread aggregation of a metastable, disease-associated subfraction of the proteome. Aggregation-prone model substrates, including expanded polyglutamine repeats, aggregate faster under these conditions. This increased aggregation results from an overload of chaperone systems, which lowers the cell-intrinsic threshold for proteins to aggregate. In line with this, we find that inhibition of the HSP70 chaperone system further exacerbates the increased protein aggregation. Moreover, we identify the molecular chaperone HSPB5 as a potent suppressor of it. Our findings reveal that various genotoxic conditions trigger protein aggregation, in a manner that is highly reminiscent of the widespread aggregation occurring in situations of proteotoxic stress and in proteinopathies.