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Neuronal Protein Homeostasis in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 June 2017) | Viewed by 72141

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Guest Editor
Pharmazentrum Frankfurt, Dept. of Clinical Pharmacology, Goethe-University of Frankfurt, Theodor Stern Kai 7, Bd. 74, 4th Fl, 60590 Frankfurt am Main, Germany
Interests: nerve injury and neuropathic pain; pain and aging; central adaptations to chronic pain; multiple sclerosis; neuroinflammation; neuro-immunologic communication; redox signaling; nitric oxide; endocannabinoids and other lipid signaling molecules; progranulin; autophagy
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Special Issue Information

Dear Colleagues,

Protein homeostasis is crucial for the maintenance of neuronal integrity and functions. Disturbances are associated with premature aging, neurodegenerative and neuropsychiatric diseases or inability to adapt to mild stresses. Such defects may be caused by pathological aggregrate-prone proteins, such as α synuclein, but, more frequently, subtle changes progressively develop because of inefficient protein folding or removal pathways involving, e.g., chaperones, proteins of the autophagy machinery, or ubiquitin ligases. The protein balance is particularly challenged under stress imposed by, e.g., ischemia, nutrient deficiency, metabolic damage, infection, inflammation, axonal trauma, or immune attack, because ER stress may enhance mis-folding, and enhanced loads of damaged proteins need to be removed to allow for regeneration and renewal. The major degradation systems include proteasome-mediated degradation, autophagy, chaperone mediated autophagy, specific ubiquitin-dependent autophagy, aggrephagy or exosomal release, which may all contribute to preconditioning adaptations during mild stress or endogenous repair after injury. In the present Special Issue, we invite contributions related to protein homeostasis in neurons and neurological diseases.

Prof. Dr. Irmgard Tegeder
Guest Editor

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Keywords

  • Chaperone
  • ER stress
  • Autophagy
  • Ubiquitin
  • Proteasome
  • Lysosome
  • Protein aggregate
  • Nerve injury
  • Protein folding
  • Aging

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Published Papers (8 papers)

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Research

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4160 KiB  
Article
Detailed Characterization of Sympathetic Chain Ganglia (SChG) Neurons Supplying the Skin of the Porcine Hindlimb
by Anna Kozłowska, Anita Mikołajczyk and Mariusz Majewski
Int. J. Mol. Sci. 2017, 18(7), 1463; https://doi.org/10.3390/ijms18071463 - 7 Jul 2017
Cited by 5 | Viewed by 9677
Abstract
It is generally known that in the skin sympathetic fibers innervate various dermal structures, including sweat glands, blood vessels, arrectores pilorum muscles and hair follicles. However, there is a lack of data about the distribution and chemical phenotyping of the sympathetic chain ganglia [...] Read more.
It is generally known that in the skin sympathetic fibers innervate various dermal structures, including sweat glands, blood vessels, arrectores pilorum muscles and hair follicles. However, there is a lack of data about the distribution and chemical phenotyping of the sympathetic chain ganglia (SChG) neurons projecting to the skin of the pig, a model that is physiologically and anatomically very representative for humans. Thus, the present study was designed to establish the origin of the sympathetic fibers supplying the porcine skin of the hind leg, and the pattern(s) of putative co-incidence of dopamine-β-hydroxylase (DβH) with pituitary adenylate cyclase-activating polypeptide (PACAP), somatostatin (SOM), neuronal nitric oxide synthase, substance P, vasoactive intestinal peptide, neuropeptide Y (NPY), leu5-enkephalin and galanin (GAL) using combined retrograde tracing and double-labeling immunohistochemistry. The Fast Blue-positive neurons were found in the L2–S2 ganglia. Most of them were small-sized and contained DβH with PACAP, SOM, NPY or GAL. The findings of the present study provide a detailed description of the distribution and chemical coding of the SChG neurons projecting to the skin of the porcine hind leg. Such data may be the basis for further studies concerning the plasticity of these ganglia under experimental or pathological conditions. Full article
(This article belongs to the Special Issue Neuronal Protein Homeostasis in Health and Disease)
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2165 KiB  
Article
BAG2 Interferes with CHIP-Mediated Ubiquitination of HSP72
by Bianca Schönbühler, Verena Schmitt, Heike Huesmann, Andreas Kern, Martin Gamerdinger and Christian Behl
Int. J. Mol. Sci. 2017, 18(1), 69; https://doi.org/10.3390/ijms18010069 - 30 Dec 2016
Cited by 12 | Viewed by 6452
Abstract
The maintenance of cellular proteostasis is dependent on molecular chaperones and protein degradation pathways. Chaperones facilitate protein folding, maturation, and degradation, and the particular fate of a misfolded protein is determined by the interaction of chaperones with co-chaperones. The co-factor CHIP (C-terminus of [...] Read more.
The maintenance of cellular proteostasis is dependent on molecular chaperones and protein degradation pathways. Chaperones facilitate protein folding, maturation, and degradation, and the particular fate of a misfolded protein is determined by the interaction of chaperones with co-chaperones. The co-factor CHIP (C-terminus of HSP70-inteacting protein, STUB1) ubiquitinates chaperone substrates and directs proteins to the cellular degradation systems. The activity of CHIP is regulated by two co-chaperones, BAG2 and HSPBP1, which are potent inhibitors of the E3 ubiquitin ligase activity. Here, we examined the functional correlation of HSP72, CHIP, and BAG2, employing human primary fibroblasts. We showed that HSP72 is a substrate of CHIP and that BAG2 efficiently prevented the ubiquitination of HSP72 in young cells as well as aged cells. Aging is associated with a decline in proteostasis and we observed increased protein levels of CHIP as well as BAG2 in senescent cells. Interestingly, the ubiquitination of HSP72 was strongly reduced during aging, which revealed that BAG2 functionally counteracted the increased levels of CHIP. Interestingly, HSPBP1 protein levels were down-regulated during aging. The data presented here demonstrates that the co-chaperone BAG2 influences HSP72 protein levels and is an important modulator of the ubiquitination activity of CHIP in young as well as aged cells. Full article
(This article belongs to the Special Issue Neuronal Protein Homeostasis in Health and Disease)
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2509 KiB  
Article
Novel Redox-Dependent Esterase Activity (EC 3.1.1.2) for DJ-1: Implications for Parkinson’s Disease
by Emmanuel Vázquez-Mayorga, Ángel G. Díaz-Sánchez, Ruben K. Dagda, Carlos A. Domínguez-Solís, Raul Y. Dagda, Cynthia K. Coronado-Ramírez and Alejandro Martínez-Martínez
Int. J. Mol. Sci. 2016, 17(8), 1346; https://doi.org/10.3390/ijms17081346 - 22 Aug 2016
Cited by 17 | Viewed by 9112
Abstract
Mutations the in human DJ-1 (hDJ-1) gene are associated with early-onset autosomal recessive forms of Parkinson’s disease (PD). hDJ-1/parkinsonism associated deglycase (PARK7) is a cytoprotective multi-functional protein that contains a conserved cysteine-protease domain. Given that cysteine-proteases can act on both amide [...] Read more.
Mutations the in human DJ-1 (hDJ-1) gene are associated with early-onset autosomal recessive forms of Parkinson’s disease (PD). hDJ-1/parkinsonism associated deglycase (PARK7) is a cytoprotective multi-functional protein that contains a conserved cysteine-protease domain. Given that cysteine-proteases can act on both amide and ester substrates, we surmised that hDJ-1 possessed cysteine-mediated esterase activity. To test this hypothesis, hDJ-1 was overexpressed, purified and tested for activity towards 4-nitrophenyl acetate (pNPA) as µmol of pNPA hydrolyzed/min/mg·protein (U/mg protein). hDJ-1 showed maximum reaction velocity esterase activity (Vmax = 235.10 ± 12.00 U/mg protein), with a sigmoidal fit (S0.5 = 0.55 ± 0.040 mM) and apparent positive cooperativity (Hill coefficient of 2.05 ± 0.28). A PD-associated mutant of DJ-1 (M26I) lacked activity. Unlike its protease activity which is inactivated by reactive oxygen species (ROS), esterase activity of hDJ-1 is enhanced upon exposure to low concentrations of hydrogen peroxide (<10 µM) and plateaus at elevated concentrations (>100 µM) suggesting that its activity is resistant to oxidative stress. Esterase activity of DJ-1 requires oxidation of catalytic cysteines, as chemically protecting cysteines blocked its activity whereas an oxido-mimetic mutant of DJ-1 (C106D) exhibited robust esterase activity. Molecular docking studies suggest that C106 and L126 within its catalytic site interact with esterase substrates. Overall, our data show that hDJ-1 contains intrinsic redox-sensitive esterase activity that is abolished in a PD-associated mutant form of the hDJ-1 protein. Full article
(This article belongs to the Special Issue Neuronal Protein Homeostasis in Health and Disease)
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Review

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4198 KiB  
Review
Reduced Abundance and Subverted Functions of Proteins in Prion-Like Diseases: Gained Functions Fascinate but Lost Functions Affect Aetiology
by W. Ted Allison, Michèle G. DuVal, Kim Nguyen-Phuoc and Patricia L. A. Leighton
Int. J. Mol. Sci. 2017, 18(10), 2223; https://doi.org/10.3390/ijms18102223 - 24 Oct 2017
Cited by 11 | Viewed by 7136
Abstract
Prions have served as pathfinders that reveal many aspects of proteostasis in neurons. The recent realization that several prominent neurodegenerative diseases spread via a prion-like mechanism illuminates new possibilities for diagnostics and therapeutics. Thus, key proteins in Alzheimer Disease and Amyotrophic lateral sclerosis [...] Read more.
Prions have served as pathfinders that reveal many aspects of proteostasis in neurons. The recent realization that several prominent neurodegenerative diseases spread via a prion-like mechanism illuminates new possibilities for diagnostics and therapeutics. Thus, key proteins in Alzheimer Disease and Amyotrophic lateral sclerosis (ALS), including amyloid-β precursor protein, Tau and superoxide dismutase 1 (SOD1), spread to adjacent cells in their misfolded aggregated forms and exhibit template-directed misfolding to induce further misfolding, disruptions to proteostasis and toxicity. Here we invert this comparison to ask what these prion-like diseases can teach us about the broad prion disease class, especially regarding the loss of these key proteins’ function(s) as they misfold and aggregate. We also consider whether functional amyloids might reveal a role for subverted protein function in neurodegenerative disease. Our synthesis identifies SOD1 as an exemplar of protein functions being lost during prion-like protein misfolding, because SOD1 is inherently unstable and loses function in its misfolded disease-associated form. This has under-appreciated parallels amongst the canonical prion diseases, wherein the normally folded prion protein, PrPC, is reduced in abundance in fatal familial insomnia patients and during the preclinical phase in animal models, apparently via proteostatic mechanisms. Thus while template-directed misfolding and infectious properties represent gain-of-function that fascinates proteostasis researchers and defines (is required for) the prion(-like) diseases, loss and subversion of the functions attributed to hallmark proteins in neurodegenerative disease needs to be integrated into design towards effective therapeutics. We propose experiments to uniquely test these ideas. Full article
(This article belongs to the Special Issue Neuronal Protein Homeostasis in Health and Disease)
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2206 KiB  
Review
Critical Roles of Dual-Specificity Phosphatases in Neuronal Proteostasis and Neurological Diseases
by Noopur Bhore, Bo-Jeng Wang, Yun-Wen Chen and Yung-Feng Liao
Int. J. Mol. Sci. 2017, 18(9), 1963; https://doi.org/10.3390/ijms18091963 - 13 Sep 2017
Cited by 21 | Viewed by 8002
Abstract
Protein homeostasis or proteostasis is a fundamental cellular property that encompasses the dynamic balancing of processes in the proteostasis network (PN). Such processes include protein synthesis, folding, and degradation in both non-stressed and stressful conditions. The role of the PN in neurodegenerative disease [...] Read more.
Protein homeostasis or proteostasis is a fundamental cellular property that encompasses the dynamic balancing of processes in the proteostasis network (PN). Such processes include protein synthesis, folding, and degradation in both non-stressed and stressful conditions. The role of the PN in neurodegenerative disease is well-documented, where it is known to respond to changes in protein folding states or toxic gain-of-function protein aggregation. Dual-specificity phosphatases have recently emerged as important participants in maintaining balance within the PN, acting through modulation of cellular signaling pathways that are involved in neurodegeneration. In this review, we will summarize recent findings describing the roles of dual-specificity phosphatases in neurodegeneration and offer perspectives on future therapeutic directions. Full article
(This article belongs to the Special Issue Neuronal Protein Homeostasis in Health and Disease)
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449 KiB  
Review
Autophagy and Human Neurodegenerative Diseases—A Fly’s Perspective
by Myungjin Kim, Allison Ho and Jun Hee Lee
Int. J. Mol. Sci. 2017, 18(7), 1596; https://doi.org/10.3390/ijms18071596 - 23 Jul 2017
Cited by 27 | Viewed by 8393
Abstract
Neurodegenerative diseases in humans are frequently associated with prominent accumulation of toxic protein inclusions and defective organelles. Autophagy is a process of bulk lysosomal degradation that eliminates these harmful substances and maintains the subcellular environmental quality. In support of autophagy’s importance in neuronal [...] Read more.
Neurodegenerative diseases in humans are frequently associated with prominent accumulation of toxic protein inclusions and defective organelles. Autophagy is a process of bulk lysosomal degradation that eliminates these harmful substances and maintains the subcellular environmental quality. In support of autophagy’s importance in neuronal homeostasis, several genetic mutations that interfere with autophagic processes were found to be associated with familial neurodegenerative disorders. In addition, genetic mutations in autophagy-regulating genes provoked neurodegenerative phenotypes in animal models. The Drosophila model significantly contributed to these recent developments, which led to the theory that autophagy dysregulation is one of the major underlying causes of human neurodegenerative disorders. In the current review, we discuss how studies using Drosophila enhanced our understanding of the relationship between autophagy and neurodegenerative processes. Full article
(This article belongs to the Special Issue Neuronal Protein Homeostasis in Health and Disease)
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1460 KiB  
Review
Proteostasis of Huntingtin in Health and Disease
by Seda Koyuncu, Azra Fatima, Ricardo Gutierrez-Garcia and David Vilchez
Int. J. Mol. Sci. 2017, 18(7), 1568; https://doi.org/10.3390/ijms18071568 - 19 Jul 2017
Cited by 37 | Viewed by 10999
Abstract
Huntington’s disease (HD) is a fatal neurodegenerative disorder characterized by motor dysfunction, cognitive deficits and psychosis. HD is caused by mutations in the Huntingtin (HTT) gene, resulting in the expansion of polyglutamine (polyQ) repeats in the HTT protein. Mutant HTT is [...] Read more.
Huntington’s disease (HD) is a fatal neurodegenerative disorder characterized by motor dysfunction, cognitive deficits and psychosis. HD is caused by mutations in the Huntingtin (HTT) gene, resulting in the expansion of polyglutamine (polyQ) repeats in the HTT protein. Mutant HTT is prone to aggregation, and the accumulation of polyQ-expanded fibrils as well as intermediate oligomers formed during the aggregation process contribute to neurodegeneration. Distinct protein homeostasis (proteostasis) nodes such as chaperone-mediated folding and proteolytic systems regulate the aggregation and degradation of HTT. Moreover, polyQ-expanded HTT fibrils and oligomers can lead to a global collapse in neuronal proteostasis, a process that contributes to neurodegeneration. The ability to maintain proteostasis of HTT declines during the aging process. Conversely, mechanisms that preserve proteostasis delay the onset of HD. Here we will review the link between proteostasis, aging and HD-related changes. Full article
(This article belongs to the Special Issue Neuronal Protein Homeostasis in Health and Disease)
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750 KiB  
Review
Potential Modes of Intercellular α-Synuclein Transmission
by Dario Valdinocci, Rowan A. W. Radford, Sue Maye Siow, Roger S. Chung and Dean L. Pountney
Int. J. Mol. Sci. 2017, 18(2), 469; https://doi.org/10.3390/ijms18020469 - 22 Feb 2017
Cited by 84 | Viewed by 11238
Abstract
Intracellular aggregates of the α-synuclein protein result in cell loss and dysfunction in Parkinson’s disease and atypical Parkinsonism, such as multiple system atrophy and dementia with Lewy bodies. Each of these neurodegenerative conditions, known collectively as α-synucleinopathies, may be characterized by a different [...] Read more.
Intracellular aggregates of the α-synuclein protein result in cell loss and dysfunction in Parkinson’s disease and atypical Parkinsonism, such as multiple system atrophy and dementia with Lewy bodies. Each of these neurodegenerative conditions, known collectively as α-synucleinopathies, may be characterized by a different suite of molecular triggers that initiate pathogenesis. The mechanisms whereby α-synuclein aggregates mediate cytotoxicity also remain to be fully elucidated. However, recent studies have implicated the cell-to-cell spread of α-synuclein as the major mode of disease propagation between brain regions during disease progression. Here, we review the current evidence for different modes of α-synuclein cellular release, movement and uptake, including exocytosis, exosomes, tunneling nanotubes, glymphatic flow and endocytosis. A more detailed understanding of the major modes by which α-synuclein pathology spreads throughout the brain may provide new targets for therapies that halt the progression of disease. Full article
(This article belongs to the Special Issue Neuronal Protein Homeostasis in Health and Disease)
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