Living with the enemy: from protein-misfolding pathologies we know, to those we want to know

Emwas, Abdul‐Hamid; Alghrably, Mawadda; Dhahri, Manel; Sharfalddin, Abeer A.; Alsiary, Rawiah; Jaremko, Mariusz; Faa, Gavino; Campagna, Marcello; Congiu, Terenzio; Piras, Monica; Piludu, Marco; Pichiri, Giuseppina; Coni, Pierpaolo; Lachowicz, Joanna Izabela

doi:10.1016/j.arr.2021.101391

Cited by 25 publications

(14 citation statements)

References 282 publications

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“…A number of neurodegenerative diseases are attributed to protein misfolding and consequent aggregation in the nervous system, leading to neurotoxicity and cell death. Protein misfolding occurs due to a complex interaction between environmental, genetic and age-related factors which influence the physicochemical state of the body, leading to impaired protein synthesis, folding and clearance [ 151 ]. In PD, the main component of pathogenic Lewy bodies and Lewy neurites is α-synuclein, a natively unfolded protein with conformational flexibility, existing as monomers and oligomers in healthy cells where it is involved in neurotransmitter release, synaptic transmission, and mitochondrial and lysosomal function [ 152 ].…”

Section: Tlrs and α-Synucleinmentioning

confidence: 99%

TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut

Gorecki

Anyaegbu

Anderton

2021

Transl Neurodegener

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Parkinson’s disease (PD) is an incurable, devastating disorder that is characterized by pathological protein aggregation and neurodegeneration in the substantia nigra. In recent years, growing evidence has implicated the gut environment and the gut-brain axis in the pathogenesis and progression of PD, especially in a subset of people who exhibit prodromal gastrointestinal dysfunction. Specifically, perturbations of gut homeostasis are hypothesized to contribute to α-synuclein aggregation in enteric neurons, which may spread to the brain over decades and eventually result in the characteristic central nervous system manifestations of PD, including neurodegeneration and motor impairments. However, the mechanisms linking gut disturbances and α-synuclein aggregation are still unclear. A plethora of research indicates that toll-like receptors (TLRs), especially TLR2 and TLR4, are critical mediators of gut homeostasis. Alongside their established role in innate immunity throughout the body, studies are increasingly demonstrating that TLR2 and TLR4 signalling shapes the development and function of the gut and the enteric nervous system. Notably, TLR2 and TLR4 are dysregulated in patients with PD, and may thus be central to early gut dysfunction in PD. To better understand the putative contribution of intestinal TLR2 and TLR4 dysfunction to early α-synuclein aggregation and PD, we critically discuss the role of TLR2 and TLR4 in normal gut function as well as evidence for altered TLR2 and TLR4 signalling in PD, by reviewing clinical, animal model and in vitro research. Growing evidence on the immunological aetiology of α-synuclein aggregation is also discussed, with a focus on the interactions of α-synuclein with TLR2 and TLR4. We propose a conceptual model of PD pathogenesis in which microbial dysbiosis alters the permeability of the intestinal barrier as well as TLR2 and TLR4 signalling, ultimately leading to a positive feedback loop of chronic gut dysfunction promoting α-synuclein aggregation in enteric and vagal neurons. In turn, α-synuclein aggregates may then migrate to the brain via peripheral nerves, such as the vagal nerve, to contribute to neuroinflammation and neurodegeneration typically associated with PD.

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Section: Tlrs and α-Synucleinmentioning

confidence: 99%

TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut

Gorecki

Anyaegbu

Anderton

2021

Transl Neurodegener

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“…Zinc is commonly used in the treatment of patients with documented zinc deficiency, which occurs in many types of liver disease, anorexia, anemia, growth retardation, abnormal immune function, abnormal nitrogen metabolism, hypogeusia, impaired reproductive capacity, coarse and sparse hair growth, flaking seborrhea of the skin, impaired connective tissue metabolism, behavioral defect, hypogonadism, and geophagia [16]. Recent studies put emphasis on zinc dyshomeostasis in neurological disorders [17] (e.g., brain injury, stroke, seizure, neurodegeneration [18]), α-1 antitrypsin polymorphism [19] and diabetes [20,21].…”

Section: Introductionmentioning

confidence: 99%

Zinc as a Drug for Wilson’s Disease, Non-Alcoholic Liver Disease and COVID-19-Related Liver Injury

et al. 2021

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Zinc is the second most abundant trace element in the human body, and it plays a fundamental role in human physiology, being an integral component of hundreds of enzymes and transcription factors. The discovery that zinc atoms may compete with copper for their absorption in the gastrointestinal tract let to introduce zinc in the therapy of Wilson’s disease, a congenital disorder of copper metabolism characterized by a systemic copper storage. Nowadays, zinc salts are considered one of the best therapeutic approach in patients affected by Wilson’s disease. On the basis of the similarities, at histological level, between Wilson’s disease and non-alcoholic liver disease, zinc has been successfully introduced in the therapy of non-alcoholic liver disease, with positive effects both on insulin resistance and oxidative stress. Recently, zinc deficiency has been indicated as a possible factor responsible for the susceptibility of elderly patients to undergo infection by SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic. Here, we present the data correlating zinc deficiency with the insurgence and progression of Covid-19 with low zinc levels associated with severe disease states. Finally, the relevance of zinc supplementation in aged people at risk for SARS-CoV-2 is underlined, with the aim that the zinc-based drug, classically used in the treatment of copper overload, might be recorded as one of the tools reducing the mortality of COVID-19, particularly in elderly people.

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“…Finally, it is important to point out that the aggregation mechanisms in vivo can be decisively influenced by additional factors, such as pH and metal ion concentrations [ 72 ] and other proteins [ 73 ]. Thus, the complete validation of the biological relevance of the mechanism for p53 aggregation proposed here would require in vivo testing, probably employing the full range of existing testing techniques [ 74 ].…”

Section: Resultsmentioning

confidence: 99%

Interdiction in the Early Folding of the p53 DNA-Binding Domain Leads to Its Amyloid-Like Misfolding

Bergasa-Caceres¹,

Rabitz²

2022

Molecules

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In this article, we investigate two issues: (a) the initial contact formation events along the folding pathway of the DNA-binding domain of the tumor suppressor protein p53 (core p53); and (b) the intermolecular events leading to its conversion into a prion-like form upon incubation with peptide P8(250-257). In the case of (a), the calculations employ the sequential collapse model (SCM) to identify the segments involved in the initial contact formation events that nucleate the folding pathway. The model predicts that there are several possible initial non-local contacts of comparative stability. The most stable of these possible initial contacts involve the protein segments 159AMAIY163 and 251ILTII255, and it is the only native-like contact. Thus, it is predicted to constitute “Nature’s shortcut” to the native structure of the core domain of p53. In the case of issue (b), these findings are then combined with experimental evidence showing that the incubation of the core domain of p53 with peptide P8(250-257), which is equivalent to the native protein segment 250PILTIITL257, leads to an amyloid conformational transition. It is explained how the SCM predicts that P8(250-257) effectively interdicts in the formation of the most stable possible initial contact and, thereby, disrupts the subsequent normal folding. Interdiction by polymeric P8(250-257) seeds is also studied. It is then hypothesized that enhanced folding through one or several of the less stable contacts could play a role in P8(250-257)-promoted core p53 amyloid misfolding. These findings are compared to previous results obtained for the prion protein. Experiments are proposed to test the hypothesis presented regarding core p53 amyloid misfolding.

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Living with the enemy: from protein-misfolding pathologies we know, to those we want to know

Cited by 25 publications

References 282 publications

TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut

TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut

Zinc as a Drug for Wilson’s Disease, Non-Alcoholic Liver Disease and COVID-19-Related Liver Injury

Interdiction in the Early Folding of the p53 DNA-Binding Domain Leads to Its Amyloid-Like Misfolding

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