Adapting the proteostasis capacity to sustain brain healthspan

Hetz, Claudio

doi:10.1016/j.cell.2021.02.007

Cited by 77 publications

(66 citation statements)

References 145 publications

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“…The α1 subunit interactomes were identified using the SILAC ratio with arbitrary yet strict criteria to remove potential false positives. To be included as an interactor, it must (1) have a SILAC ratio of WT α1/EV or α1(A322D)/EV to be at least 1.30; (2) have a p < 0.05; and (3) have a Benjamini and Hochberg correction (35) of false discovery rate (FDR) of no more than 0.10. The top right green area in Figure 2A contains high-confidence interactors for GABA A receptors.…”

Section: Resultsmentioning

confidence: 99%

“…Normal organismal physiology depends on the maintenance of protein homeostasis (proteostasis) in each cellular compartment (1)(2)(3)(4), which dictates a delicate balance between protein synthesis, folding, assembly, trafficking, and degradation while minimizing misfolding and aggregation (5)(6)(7). For one specific client protein, its interaction with a network of proteins, especially its proteostasis network components, in the crowded cellular environment is critical to maintain its proteostasis.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative interactome proteomics identifies proteostasis network for GABA_Areceptors

Wang

2022

Preprint

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Gamma-aminobutyric acid type A (GABAA) receptors, the primary inhibitory neurotransmitter-gated ion channels in the mammalian central nervous system, inhibit neuronal firing to preserve balanced neuronal activity. Maintenance of GABAA receptor protein homeostasis (proteostasis) in the cell utilizing its interacting proteins is essential for the function of GABAA receptors. However, how the proteostasis network orchestrates GABAA receptor biogenesis in the endoplasmic reticulum (ER) is not well understood. To address this question systematically, we employed a proteomics-based approach to identify the interactomes of GABAA receptors by carrying out a quantitative immunoprecipitation-tandem mass spectrometry (IP-MS/MS) analysis utilizing stable isotope labeling by amino acids in cell culture (SILAC). To enhance the coverage and reliability of the identified proteins, we performed comparative proteomics by using both wild type alpha1 subunit and a misfolding-prone alpha1 subunit carrying the A322D variant as the bait proteins. The wild type alpha1 interactome contains 125 proteins, the alpha1(A322D) interactome contains 105 proteins, and 54 proteins overlap within two interactomes. Bioinformatics analysis identified potential GABAA receptor proteostasis network components, including chaperones, folding enzymes, trafficking factors, and degradation factors. Further, their potential involvement is modelled in the cellular folding, degradation and trafficking pathways for GABAA receptors. In addition, we verified endogenous interactions between alpha1 subunit and their selected interactors by carrying out co-immunoprecipitation assay in mouse brain homogenates. This study paves the way for understanding the molecular mechanisms as well as fine-tuning of GABAA receptor proteostasis to ameliorate related neurological diseases such as epilepsy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quantitative interactome proteomics identifies proteostasis network for GABA_Areceptors

Wang

2022

Preprint

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“…Variants in genes of the glycosylation pathway are linked to congenital disorders, but underlying pathogenic mechanisms remain poorly defined (Freeze et al , 2015). Other nodes of the proteostasis network such as autophagy and protein translation control have been also associated with neurodevelopmental disorders (Hetz, 2021). Interestingly, the activity of the UPR has been recently suggested to contribute to normal nervous system development, highlighting the regulation of brain architecture through the control of neurogenesis, cortical neurons migration, and neuronal differentiation (Martínez et al , 2018; Urra et al , 2018).…”

Section: Discussionmentioning

confidence: 99%

Mutation in protein disulfide isomerase A3 causes neurodevelopmental defects by disturbing endoplasmic reticulum proteostasis

et al. 2021

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Recessive gene mutations underlie many developmental disorders and often lead to disabling neurological problems. Here, we report identification of a homozygous c.170G>A (p.Cys57Tyr or C57Y) mutation in the gene coding for protein disulfide isomerase A3 (PDIA3, also known as ERp57), an enzyme that catalyzes formation of disulfide bonds in the endoplasmic reticulum, to be associated with syndromic intellectual disability. Experiments in zebrafish embryos show that PDIA3 C57Y expression is pathogenic and causes developmental defects such as axonal disorganization as well as skeletal abnormalities. Expression of PDIA3 C57Y in the mouse hippocampus results in impaired synaptic plasticity and memory consolidation. Proteomic and functional analyses reveal that PDIA3 C57Y expression leads to dysregulation of cell adhesion and actin cytoskeleton dynamics, associated with altered integrin biogenesis and reduced neuritogenesis. Biochemical studies show that PDIA3 C57Y has decreased catalytic activity and forms disulfide-crosslinked aggregates that abnormally interact with chaperones in the endoplasmic reticulum. Thus, rare disease gene variant can provide insight into how perturbations of neuronal proteostasis can affect the function of the nervous system.

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“…Remarkably, the capacity of the UPR to set the threshold between cell survival and death has associated the pathway with several neurodegenerative diseases that are typified by abnormal protein aggregation (Hetz, 2021). Nevertheless, despite this evidence, it is unclear if the UPR is selectively regulated at the level of supporting cells, nerve cells, and immune cells residing in the brain.…”

Section: Introductionmentioning

confidence: 99%

The Unfolded Protein Response in Immune Cells as an Emerging Regulator of Neuroinflammation

Fernández

Geisse

Bernales

et al. 2021

Front. Aging Neurosci.

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Immune surveillance is an essential process that safeguards the homeostasis of a healthy brain. Among the increasing diversity of immune cells present in the central nervous system (CNS), microglia have emerged as a prominent leukocyte subset with key roles in the support of brain function and in the control of neuroinflammation. In fact, impaired microglial function is associated with the development of neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). Interestingly, these pathologies are also typified by protein aggregation and proteostasis dysfunction at the level of the endoplasmic reticulum (ER). These processes trigger activation of the unfolded protein response (UPR), which is a conserved signaling network that maintains the fidelity of the cellular proteome. Remarkably, beyond its role in protein folding, the UPR has also emerged as a key regulator of the development and function of immune cells. However, despite this evidence, the contribution of the UPR to immune cell homeostasis, immune surveillance, and neuro-inflammatory processes remains largely unexplored. In this review, we discuss the potential contribution of the UPR in brain-associated immune cells in the context of neurodegenerative diseases.

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Adapting the proteostasis capacity to sustain brain healthspan

Cited by 77 publications

References 145 publications

Quantitative interactome proteomics identifies proteostasis network for GABA_Areceptors

Quantitative interactome proteomics identifies proteostasis network for GABA_Areceptors

Mutation in protein disulfide isomerase A3 causes neurodevelopmental defects by disturbing endoplasmic reticulum proteostasis

The Unfolded Protein Response in Immune Cells as an Emerging Regulator of Neuroinflammation

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Adapting the proteostasis capacity to sustain brain healthspan

Cited by 77 publications

References 145 publications

Quantitative interactome proteomics identifies proteostasis network for GABAAreceptors

Quantitative interactome proteomics identifies proteostasis network for GABAAreceptors

Mutation in protein disulfide isomerase A3 causes neurodevelopmental defects by disturbing endoplasmic reticulum proteostasis

The Unfolded Protein Response in Immune Cells as an Emerging Regulator of Neuroinflammation

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Quantitative interactome proteomics identifies proteostasis network for GABA_Areceptors

Quantitative interactome proteomics identifies proteostasis network for GABA_Areceptors