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Genetic variation in human populations can result in the misfolding and aggregation of proteins, giving rise to systemic and neurodegenerative diseases that require management by proteostasis. Here, we define the role of GRP94, the endoplasmic reticulum Hsp90 chaperone paralog, in managing alpha-1-antitrypsin deficiency on a residue-by-residue basis using Gaussian process regression-based machine learning to profile the spatial covariance relationships that dictate protein folding arising from sequence variants in the population. Covariance analysis suggests a role for the ATPase activity of GRP94 in controlling the N- to C-terminal cooperative folding of alpha-1-antitrypsin responsible for the correction of liver aggregation and lung-disease phenotypes of alpha-1-antitrypsin deficiency. Gaussian process-based spatial covariance profiling provides a standard model built on covariant principles to evaluate the role of proteostasis components in guiding information flow from genome to proteome in response to genetic variation, potentially allowing us to intervene in the onset and progression of complex multi-system human diseases. Pei et al. applied Gaussian process-based machine learning to capture dynamic spatial covariance relationships managed by proteostasis to mediate cooperative folding on a residue basis as a standard model for precision disease management. [ABSTRACT FROM AUTHOR]

Environmental context: Pesticides are critical to agriculture and food production but require ecological risk assessments. Although most risk assessments require data from vertebrate animal testing, we have developed an approach to assess risk to fish, birds and mammals using other means. This approach could help to ensure protection of the environment while minimising animal testing. Rationale: Recent directives to reduce animal testing have implications for ecological risk assessment, as several vertebrate tests are used to support these assessments. Therefore, a modern approach was devised to address these key knowledge needs without the use of chemical-specific vertebrate testing. Methodology: An ecological risk assessment for a novel acetyl-coenzyme A carboxylase (ACCase) inhibitor herbicide was conducted using alternative lines of evidence. For fish, chemical toxicity distributions were constructed to quantify the probability of effects, and these distributions were compared with exposure estimates for a representative use in soybeans. The effect distributions were further refined based on invertebrate toxicity and partitioning behaviour. For birds and mammals, a joint probability curve was constructed by integrating chemical toxicity distributions and Kenaga exposure distributions. Results: The lines of evidence presented in this predictive risk assessment suggest the intended use of a new ACCase inhibitor is unlikely to affect fish, birds, or mammals. Exposure was unlikely to exceed effect estimates, regardless of whether they were derived based on chemical-read across, invertebrate toxicity, or partitioning behaviour. Discussion: Key knowledge needs for ecological risk assessment can be informed by lines of evidence that do not require animal testing. The present study demonstrates such an approach by comparing predicted exposure and effects, which are expected to be protective. This predictive approach can be extended to other active ingredients and chemical classes, as well as other taxonomic groups of interest. Future research should aim to integrate new approach methods in a predictive risk assessment framework. Environmental context. Pesticides are critical to agriculture and food production but require ecological risk assessments. Although most risk assessments require data from vertebrate animal testing, we have developed an approach to assess risk to fish, birds and mammals using other means. This approach could help to ensure protection of the environment while minimising animal testing. This article belongs to the collection NAMs in Environmental Chemistry and Toxicology. [ABSTRACT FROM AUTHOR]

Complement is an ancient and complex network of the immune system and, as such, it plays vital physiological roles, but it is also involved in numerous pathological processes. The proper regulation of the complement system is important to allow its sufficient and targeted activity without deleterious side-effects. Factor H is a major complement regulator, and together with its splice variant factor H-like protein 1 and the five human factor H-related (FHR) proteins, they have been linked to various diseases. The role of factor H in inhibiting complement activation is well studied, but the function of the FHRs is less characterized. Current evidence supports the main role of the FHRs as enhancers of complement activation and opsonization, i.e., counter-balancing the inhibitory effect of factor H. FHRs emerge as soluble pattern recognition molecules and positive regulators of the complement system. In addition, factor H and some of the FHR proteins were shown to modulate the activity of immune cells, a non-canonical function outside the complement cascade. Recent efforts have intensified to study factor H and the FHRs and develop new tools for the distinction, quantification and functional characterization of members of this protein family. Here, we provide an update and overview on the versatile roles of factor H family proteins, what we know about their biological functions in healthy conditions and in diseases. [ABSTRACT FROM AUTHOR]

Fibrosis is characterized by excessive extracellular matrix (ECM) deposition resulting from dysregulated wound healing and connective tissue repair mechanisms. Excessive accumulation of ECM leads to fibrous tissue formation, impairing organ function and driving the progression of various fibrotic diseases. Recently, the role of small ubiquitin-like modifiers (SUMO) in fibrotic diseases has attracted significant attention. SUMO-mediated SUMOylation, a highly conserved posttranslational modification, participates in a variety of biological processes, including nuclear-cytosolic transport, cell cycle progression, DNA damage repair, and cellular metabolism. Conversely, SUMO-specific proteases cleave the isopeptide bond of SUMO conjugates, thereby regulating the deSUMOylation process. Mounting evidence indicates that SUMOylation and deSUMOylation regulate the functions of several proteins, such as Smad3, NF-κB, and promyelocytic leukemia protein, which are implicated in fibrotic diseases like liver fibrosis, myocardial fibrosis, and pulmonary fibrosis. This review summarizes the role of SUMO in fibrosis-related pathways and explores its pathological relevance in various fibrotic diseases. All evidence suggest that the SUMO pathway is important targets for the development of treatments for fibrotic diseases., (© 2024 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Background and Aims: In the classical form of α1-antitrypsin deficiency, a misfolded variant α1-antitrypsin Z accumulates in the endoplasmic reticulum of liver cells and causes liver cell injury by gain-of-function proteotoxicity in a sub-group of affected homozygotes but relatively little is known about putative modifiers. Here, we carried out genomic sequencing in a uniquely affected family with an index case of liver failure and 2 homozygous siblings with minimal or no liver disease. Their sequences were compared to sequences in well-characterized cohorts of homozygotes with or without liver disease, and then candidate sequence variants were tested for changes in the kinetics of α1-antitrypsin variant Z degradation in iPS-derived hepatocyte-like cells derived from the affected siblings themselves., Approach and Results: Specific variants in autophagy genes MTMR12 and FAM134A could each accelerate the degradation of α1-antitrypsin variant Z in cells from the index patient, but both MTMR12 and FAM134A variants were needed to slow the degradation of α1-antitrypsin variant Z in cells from a protected sib, indicating that inheritance of both variants is needed to mediate the pathogenic effects of hepatic proteotoxicity at the cellular level. Analysis of homozygote cohorts showed that multiple patient-specific variants in proteostasis genes are likely to explain liver disease susceptibility at the population level., Conclusions: These results validate the concept that genetic variation in autophagy function can determine susceptibility to liver disease in α1-antitrypsin deficiency and provide evidence that polygenic mechanisms and multiple patient-specific variants are likely needed for proteotoxic pathology., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Alpha-1 antitrypsin deficiency (A1ATD) is a life-threatening condition caused by the inheritance of the serpin family A member 1 "Z" genetic variant driving alpha-1 antitrypsin (AAT) protein misfolding in hepatocytes. There are no approved medicines for this disease., Methods: We conducted a high-throughput image-based small molecule screen using patient-derived induced pluripotent stem cell-hepatocytes (iPSC-hepatocytes). Identified targets were validated in vitro using 3 independent patient iPSC lines. The effects of the identified target, leucine-rich repeat kinase 2 (LRRK2), were further evaluated in an animal model of A1ATD through histology and immunohistochemistry and in an autophagy-reporter line. Autophagy induction was assessed through immunoblot and immunofluorescence analyses., Results: Small-molecule screen performed in iPSC-hepatocytes identified LRRK2 as a potentially new therapeutic target. Of the commercially available LRRK2 inhibitors tested, we identified CZC-25146, a candidate with favorable pharmacokinetic properties, as capable of reducing polymer load, increasing normal AAT secretion, and reducing inflammatory cytokines in both cells and PiZ mice. Mechanistically, this effect was achieved through the induction of autophagy., Conclusions: Our findings support the use of CZC-25146 and leucine-rich repeat kinase-2 inhibitors in hepatic proteinopathy research and their further investigation as novel therapeutic candidates for A1ATD., (Copyright © 2024 American Association for the Study of Liver Diseases.)