Embryo integrity regulates maternal proteostasis and stress resilience

Bott, Laura C.; Brielmann, Renée M.; Morimoto, Richard I.

doi:10.1101/gad.335422.119

Cited by 26 publications

(39 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, DNA damage activates an innate immune response that in turn enhances UPS activity and proteostasis in other tissues ( Ermolaeva et al 2013 ). Finally, a recent study has indicated that developing embryos affect the proteostasis of the hermaphrodite worm carrying them ( Sala et al 2020 ). Together, these surprising observations indicate intertissue communication mechanisms that rewire organismal PNs neuron-independently ( Figure 3 ).…”

Section: Organismal Regulation Of Stress Response and Proteostasismentioning

confidence: 99%

Organismal Protein Homeostasis Mechanisms

Hoppe

Cohen

2020

Genetics

View full text Add to dashboard Cite

Sustaining a healthy proteome is a lifelong challenge for each individual cell of an organism. However, protein homeostasis or proteostasis is constantly jeopardized since damaged proteins accumulate under proteotoxic stress that originates from ever-changing metabolic, environmental, and pathological conditions. Proteostasis is achieved via a conserved network of quality control pathways that orchestrate the biogenesis of correctly folded proteins, prevent proteins from misfolding, and remove potentially harmful proteins by selective degradation. Nevertheless, the proteostasis network has a limited capacity and its collapse deteriorates cellular functionality and organismal viability, causing metabolic, oncological, or neurodegenerative disorders. While cell-autonomous quality control mechanisms have been described intensely, recent work on Caenorhabditis elegans has demonstrated the systemic coordination of proteostasis between distinct tissues of an organism. These findings indicate the existence of intricately balanced proteostasis networks important for integration and maintenance of the organismal proteome, opening a new door to define novel therapeutic targets for protein aggregation diseases. Here, we provide an overview of individual protein quality control pathways and the systemic coordination between central proteostatic nodes. We further provide insights into the dynamic regulation of cellular and organismal proteostasis mechanisms that integrate environmental and metabolic changes. The use of C. elegans as a model has pioneered our understanding of conserved quality control mechanisms important to safeguard the organismal proteome in health and disease.

show abstract

Section: Organismal Regulation Of Stress Response and Proteostasismentioning

confidence: 99%

Organismal Protein Homeostasis Mechanisms

Hoppe

Cohen

2020

Genetics

View full text Add to dashboard Cite

show abstract

“…RNA was extracted using TRIzol (Invitrogen) and purified with QIAGEN RNeasy MinElute columns as per manufacturers’ instructions. 44 mRNA was reverse transcribed using the iScript cDNA Synthesis Kit (BioRad) and real-time quantitative PCR was performed using iQ SYBR Green Supermix (BioRad) in a BioRad CFX384 Real-Time PCR system. Relative expression was determined from cycle threshold values using the standard curve method and the expression of genes of interest was normalized to cdc-42 .…”

Section: Methodsmentioning

confidence: 99%

Variants in ATP6V0A1 cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy

Bott

Forouhan

Lieto

et al. 2021

Brain Communications

View full text Add to dashboard Cite

The vacuolar H+-ATPase is a large multi-subunit proton pump, composed of an integral membrane V0 domain, involved in proton translocation, and a peripheral V1 domain, catalysing ATP hydrolysis. This complex is widely distributed on the membrane of various subcellular organelles, such as endosomes and lysosomes, and plays a critical role in cellular processes ranging from autophagy to protein trafficking and endocytosis. Variants in ATP6V0A1, the brain-enriched isoform in the V0 domain, have been recently associated with developmental delay and epilepsy in four individuals. Here, we identified 17 individuals from 14 unrelated families with both with new and previously characterized variants in this gene, representing the largest cohort to date. Five affected subjects with biallelic variants in this gene presented with a phenotype of early-onset progressive myoclonus epilepsy with ataxia, while 12 individuals carried de novo missense variants and showed severe developmental and epileptic encephalopathy. The R740Q mutation, which alone accounts for almost 50% of the mutations identified among our cases, leads to failure of lysosomal hydrolysis by directly impairing acidification of the endolysosomal compartment, causing autophagic dysfunction and severe developmental defect in Caenorhabditis elegans. Altogether, our findings further expand the neurological phenotype associated with variants in this gene and provide a direct link with endolysosomal acidification in the pathophysiology of ATP6V0A1-related conditions.

show abstract

“…The data suggest that there is an embryo-to-mother signaling pathway that regulates the balance between somatic proteostasis and quality of the progeny. 1 The next speaker was Dr. Della David (University of Tübingen, Tübingen, Germany), who presented exciting work detailing for the first time a mechanism by which C. elegans can coordinate extracellular proteostasis through the stress-activated map kinase, KGB1. She showed how the elimination of coelomocytes promotes age-dependent aggregation of lipid-binding protein 2 (LBP-2) in the C. elegans pseudocoelom.…”

Section: Of 6 | Meeting Reportmentioning

confidence: 99%