Misfolded protein aggregates: Mechanisms, structures and potential for disease transmission

Moreno-González, Inés; Soto, Claudio

doi:10.1016/j.semcdb.2011.04.002

Cited by 187 publications

(145 citation statements)

References 86 publications

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“…These include intracellular removal or processing of misfolded proteins, 15 involving cellular chaperones, the ubiquitin-proteasome system, and autophagy. Intracellular or pericellular processing of abnormal proteins is a simple way of protein elimination, but if not controlled properly, may lead to cell death, dysregulation of homeostasis, and diseases such as Huntington, 16 amyloidosis, 17 Alzheimer, 18 or Parkinson. 19 The ubiquitin-proteasome system deals primarily with endogenous proteins.…”

Section: Basic Conceptsmentioning

confidence: 99%

Heat shock response and autophagy—cooperation and control

2015

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Abbreviations: AKT, v-akt murine thymoma viral oncogene homolog 1; AMPK, adenosine monophosphate-activated protein kinase; ATG, autophagy-related; BECN1, Beclin 1, autophagy related; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; ER, endoplasmic reticulum; FOXO, forkhead box O; HSF1, heat shock transcription factor 1; HSP, heat shock protein; HSPA8/ HSC70, heat shock 70kDa protein 8; IL, interleukin; LC3, MAP1LC3, microtubule-associated protein 1 light chain 3; MTMR14/ hJumpy, myotubularin related protein 14; MTOR, mechanistic target of rapamycin; NR1D1/Rev-Erb-a, nuclear receptor subfamily 1, group D, member 1; PBMC, peripheral blood mononuclear cell; PPARGC1A/PGC-1a, peroxisome proliferator-activated receptor, gamma, coactivator 1 a; RHEB, Ras homolog enriched in brain; SOD, superoxide dismutase; SQSTM1/p62, sequestosome 1; TPR, translocated promoter region, nuclear basket protein; TSC, tuberous sclerosis complex; ULK1, unc-51 like autophagy activating kinase 1.Protein quality control (proteostasis) depends on constant protein degradation and resynthesis, and is essential for proper homeostasis in systems from single cells to whole organisms. Cells possess several mechanisms and processes to maintain proteostasis. At one end of the spectrum, the heat shock proteins modulate protein folding and repair. At the other end, the proteasome and autophagy as well as other lysosome-dependent systems, function in the degradation of dysfunctional proteins. In this review, we examine how these systems interact to maintain proteostasis. Both the direct cellular data on heat shock control over autophagy and the time course of exercise-associated changes in humans support the model that heat shock response and autophagy are tightly linked. Studying the links between exercise stress and molecular control of proteostasis provides evidence that the heat shock response and autophagy coordinate and undergo sequential activation and downregulation, and that this is essential for proper proteostasis in eukaryotic systems.

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Section: Basic Conceptsmentioning

confidence: 99%

Heat shock response and autophagy—cooperation and control

2015

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“…These nonbranching, highly aggregative filaments of 4−7 nm in diameter are resistant to degradation by proteases and denaturation by detergents and thus share biochemical and structural characteristics with amyloid fibers (3,4). Amyloid structures are better known for their involvement in disease-associated processes of protein misfolding and aggregation in humans, such as Alzheimer's disease (5)(6)(7). However, in contrast to these aberrantly folded proteins in pathogenic amyloidosis (6), bacterial curli are "functional" amyloids and are important for biofilm formation, host cell adhesion, and colonization of inert surfaces (8).…”

mentioning

confidence: 99%

Structure of the nonameric bacterial amyloid secretion channel

Cao

Zhao

Kou

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

102

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Various strains of bacteria are able to produce a unique class of functional amyloids termed curli, which are critical for biofilm formation, host cell adhesion, and colonization of inert surfaces. Curli are secreted via the type VIII bacterial secretion system, and they share biochemical and structural characteristics with amyloid fibers that have been implicated in deleterious disease in humans. Here, we report the crystal structure of Escherichia coli CsgG, which is an essential lipoprotein component of the type VIII secretion system and which forms a secretion channel in the bacterial outer membrane for transporting curli subunits. CsgG forms a crown-shaped, symmetric nonameric channel that spans the outer membrane via a 36-strand β-barrel, with each subunit contributing four β-strands. This nonameric complex contains a central channel with a pore located at the middle. The eyelet of the pore is ∼12 Å in diameter and is lined with three stacked nine-residue rings consisting of Tyr-66, Asn-70, or Phe-71. Our structure-based functional studies suggest that Tyr-66 and Phe-71 residues function as gatekeepers for the selective secretion of curli subunits. Our study describes in detail, to our knowledge, the first core structure of the type VIII bacterial secretion machinery. Importantly, our structural analysis suggests that the curli subunits are secreted via CsgG across the bacterial outer membrane in an unfolded form.CsgG | curli | amyloids | outer membrane protein | biofilm

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“…Accumulation of misfolded proteins has been implicated in diabetic embryopathy (8,9), but the fate of these misfolded proteins, which can aggregate and become cytotoxic (18), has not been previously explored. We used a Proteostat system to examine protein aggregates in the neural tube of embryos at E9.5 and E10.5.…”

Section: Significancementioning

confidence: 99%

“…Misfolded proteins are prone to forming aggregates that are resistant to UPS degradation (18). Aggregation of α-Synuclein (α-Syn), Parkin, and Huntingtin (Htt) has been found to be involved in the pathogenesis of Alzheimer's, Parkinson's, and Huntington's diseases (19)(20)(21)(22).…”

mentioning

confidence: 99%

Formation of neurodegenerative aggresome and death-inducing signaling complex in maternal diabetes-induced neural tube defects

Zhao

Cao

Reece

2017

Proc. Natl. Acad. Sci. U.S.A.

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Diabetes mellitus in early pregnancy increases the risk in infants of birth defects, such as neural tube defects (NTDs), known as diabetic embryopathy. NTDs are associated with hyperglycemia-induced protein misfolding and Caspase-8–induced programmed cell death. The present study shows that misfolded proteins are ubiquitinylated, suggesting that ubiquitin-proteasomal degradation is impaired. Misfolded proteins form aggregates containing ubiquitin-binding protein p62, suggesting that autophagic-lysosomal clearance is insufficient. Additionally, these aggregates contain the neurodegenerative disease-associated proteins α-Synuclein, Parkin, and Huntingtin (Htt). Aggregation of Htt may lead to formation of a death-inducing signaling complex of Hip1, Hippi, and Caspase-8. Treatment with chemical chaperones, such as sodium 4-phenylbutyrate (PBA), reduces protein aggregation in neural stem cells in vitro and in embryos in vivo. Furthermore, treatment with PBA in vivo decreases NTD rate in the embryos of diabetic mice, as well as Caspase-8 activation and cell death. Enhancing protein folding could be a potential interventional approach to preventing embryonic malformations in diabetic pregnancies.

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Misfolded protein aggregates: Mechanisms, structures and potential for disease transmission

Cited by 187 publications

References 86 publications

Heat shock response and autophagy—cooperation and control

Heat shock response and autophagy—cooperation and control

Structure of the nonameric bacterial amyloid secretion channel

Formation of neurodegenerative aggresome and death-inducing signaling complex in maternal diabetes-induced neural tube defects

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