Dataset Information

Hyperactive 20S Proteasome Enhances Proteostasis and ERAD in C. elegans via degradation of Intrinsically Disordered Proteins

ABSTRACT: Age-related proteinopathies, including Alzheimer’s and Parkinson’s disease, are driven by toxic accumulation of misfolded and intrinsically disordered proteins (IDPs) that overwhelm cellular proteostasis. The proteasome clears these proteins, but its failure in disease remains unclear. We engineered a Caenorhabditis elegans model with a hyperactive 20S proteasome (α3ΔN) for selective 20S activation. α3ΔN markedly enhanced IDP and misfolded protein degradation, reduced oxidative damage, and improved endoplasmic reticulum associated degradation (ERAD). Aggregation prone substrates such as vitellogenins and human alpha-1 antitrypsin (ATZ) were efficiently cleared. Integrated proteomic and transcriptomic analyses reveal systemic adaptations featuring increased protein turnover and oxidative stress resistance independent of superoxide dismutases (SODs). Strikingly, α3ΔN extended lifespan and stress resistance independently of canonical unfolded protein response (UPR) signaling via xbp 1. These findings substantiate a “20S pathway” of proteostasis that directly alleviates protein aggregation and oxidative stress, offering a promising therapeutic angle for neurodegenerative diseases

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ORGANISM(S): Caenorhabditis Elegans

TISSUE(S): Whole Body

SUBMITTER: David Salcedo Tacuma

LAB HEAD: David M.Smith

PROVIDER: PXD055640 | Pride | 2025-07-23

REPOSITORIES: Pride

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Hyperactive 20S Proteasome Enhances Proteostasis and ERAD in <i>C. elegans</i> via degradation of Intrinsically Disordered Proteins.

Salcedo-Tacuma David D Asad Nadeem N Anderson Raymond R Smith David M DM

bioRxiv : the preprint server for biology 20250409

Age-related proteinopathies, including Alzheimer's and Parkinson's disease, are driven by the toxic accumulation of misfolded proteins, particularly intrinsically disordered proteins (IDPs), that overwhelm cellular proteostasis. The proteasome is responsible for the clearance of these proteins, but it is unclear why it fails to do so in these diseases. Here, we report a novel strategy employing a <i>C. elegans</i> model with a hyperactive 20S proteasome (α3ΔN) to achieve selective activation. Th ...[more]

PMID: 38617285

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Project description:Polycystic liver disease (PLD) is a group of genetic disorders characterized by bile duct dilatation and/or progressive development of multiple intrahepatic fluid-filled biliary cysts (>10), which are the main cause of morbidity. Current surgical and/or pharmacological therapies exert short-term and modest benefits, and thus liver transplantation represents the only curative option. Recently, novel PLD-causative genes, encoding for endoplasmic reticulum (ER)-resident proteins involved in protein biogenesis and transport, were identified. Here, we hypothesized that aberrant proteostasis contributes to PLD pathogenesis, representing a potential therapeutic target. In this regard, ER stress was assessed at transcriptional (qPCR), proteomic (mass spectrometry), morphological (transmission electron microscopy; TEM) and functional (20S proteasome activity) levels in different models of PLD (i.e., human and rat). Moreover, PCK rat (animal model of PLD) was employed to determine the effects of ER stress inhibitors [4-phenylbutyric acid (4-PBA)] and/or inducers [tunicamycin (TM)] in hepatic cytogenesis and, consequently, in the progression of the disease. Likewise, the impact of the aforementioned ER stress modulators was also analyzed on the expression of unfolded protein response (UPR) factors, the 20S proteasome activity, the mechanisms involved in the maintenance of ER proteostasis and the cell fate decisions (i.e., survival/apoptosis). Interestingly, the expression levels of the UPR factors were markedly upregulated in liver tissue from PLD patients and PCK rats, as well as in primary cultures of human and rat cystic cholangiocytes, compared to normal controls. Additionally, cystic cholangiocytes showed altered proteomic profiles, mainly related to proteostasis (i.e., synthesis, folding, trafficking and degradation of nascent proteins), marked enlargement of the ER lumen (by TEM), and hyperactivation of the 20S proteasome. Notably, chronic treatment of PCK rats with 4-PBA decreased liver weight, as well as both liver and cystic volumes, of animals under baseline or TM administration compared to control groups. In vitro, 4-PBA downregulated the expression (mRNA) of UPR effectors, normalized, at least in part, proteomic profiles related to protein synthesis, folding, trafficking and degradation, and reduced the proteasome hyperactivity in cystic cholangiocytes, reducing their hyperproliferation and apoptosis. Conclusion: Restoration of proteostasis in cystic cholangiocytes with 4-PBA halts hepatic cystogenesis, emerging as a novel and promising therapeutic strategy.

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Dataset Information

Hyperactive 20S Proteasome Enhances Proteostasis and ERAD in C. elegans via degradation of Intrinsically Disordered Proteins

Dataset's files

Publications

Hyperactive 20S Proteasome Enhances Proteostasis and ERAD in <i>C. elegans</i> via degradation of Intrinsically Disordered Proteins.

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Dataset Information

Hyperactive 20S Proteasome Enhances Proteostasis and ERAD in C. elegans via degradation of Intrinsically Disordered Proteins

Dataset's files

Publications

Hyperactive 20S Proteasome Enhances Proteostasis and ERAD in &lt;i&gt;C. elegans&lt;/i&gt; via degradation of Intrinsically Disordered Proteins.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Hyperactive 20S Proteasome Enhances Proteostasis and ERAD in <i>C. elegans</i> via degradation of Intrinsically Disordered Proteins.