scholarly journals Threshold concentration and random collision determine the growth of the phase-separated huntingtin inclusion from a stable core

2020 ◽  
Author(s):  
Sen Pei ◽  
Theresa C. Swayne ◽  
Jeffrey F. Morris ◽  
Lesley Emtage
Keyword(s):  
Growth Rate ◽  
Confocal Microscopy ◽  
Neurodegenerative Diseases ◽  
Inclusion Bodies ◽  
Threshold Concentration ◽  
Mutant Huntingtin ◽  
Unfolded Protein ◽  
Stable Core ◽  
The Relationship

AbstractThe processes underlying formation and growth of unfolded protein inclusions are relevant to neurodegenerative diseases. In S. cerevisiae, inclusion bodies formed by mutant huntingtin have characteristics of phase-separated compartments: they are mobile, ovoid, and the contents are diffusible. We have used molecular genetics and quantitative confocal microscopy to probe the relationship between concentration and inclusion growth in vivo. Our analysis and modeling of the growth of mutant huntingtin inclusion bodies (mHtt IBs) suggests that there is a cytoplasmic threshold concentration that triggers the formation of an IB, regardless of proteasome capacity, and that reduction in cytoplasmic mHtt causes IBs to shrink. These findings confirm that the IB is a phase-separated compartment that continuously exchanges material with the cytoplasm. The growth rate of the IB is most consistent with a model in which material is incorporated through collision with the IB. A small remnant of the IB is relatively long-lasting, suggesting that the IB contains a core that is structurally distinct, and which may serve to nucleate it.

scholarly journals Threshold concentration and random collision determine the growth of the huntingtin inclusion from a stable core

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Sen Pei ◽  
Theresa C. Swayne ◽  
Jeffrey F. Morris ◽  
Lesley Emtage
Keyword(s):  
Inclusion Bodies ◽  
Physical Nature ◽  
Living Cells ◽  
Threshold Concentration ◽  
Rich Mixture ◽  
Unfolded Protein ◽  
New Material ◽  
Stable Core ◽  
The Relationship

AbstractThe processes underlying formation and growth of unfolded protein inclusions are relevant to neurodegenerative diseases but poorly characterized in living cells. In S. cerevisiae, inclusions formed by mutant huntingtin (mHtt) have some characteristics of biomolecular condensates but the physical nature and growth mechanisms of inclusion bodies remain unclear. We have probed the relationship between concentration and inclusion growth in vivo and find that growth of mHtt inclusions in living cells is triggered at a cytoplasmic threshold concentration, while reduction in cytoplasmic mHtt causes inclusions to shrink. The growth rate is consistent with incorporation of new material through collision and coalescence. A small remnant of the inclusion is relatively long-lasting, suggesting that it contains a core that is structurally distinct, and which may serve to nucleate it. These observations support a model in which aggregative particles are incorporated by random collision into a phase-separated condensate composed of a particle-rich mixture.

scholarly journals Protein misfolding specifies recruitment to cytoplasmic inclusion bodies

2016 ◽  
Vol 213 (2) ◽  
pp. 229-241 ◽  
Author(s):  
Kirill Bersuker ◽  
Michael Brandeis ◽  
Ron R. Kopito
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Inclusion Bodies ◽  
Cytoplasmic Inclusion ◽  
Degradation Pathway ◽  
Mutant Huntingtin ◽  
Histopathological Features ◽  
Associated Proteins ◽  
Cytoplasmic Inclusion Bodies

Inclusion bodies (IBs) containing aggregated disease-associated proteins and polyubiquitin (poly-Ub) conjugates are universal histopathological features of neurodegenerative diseases. Ub has been proposed to target proteins to IBs for degradation via autophagy, but the mechanisms that govern recruitment of ubiquitylated proteins to IBs are not well understood. In this paper, we use conditionally destabilized reporters that undergo misfolding and ubiquitylation upon removal of a stabilizing ligand to examine the role of Ub conjugation in targeting proteins to IBs that are composed of an N-terminal fragment of mutant huntingtin, the causative protein of Huntington’s disease. We show that reporters are excluded from IBs in the presence of the stabilizing ligand but are recruited to IBs after ligand washout. However, we find that Ub conjugation is not necessary to target reporters to IBs. We also report that forced Ub conjugation by the Ub fusion degradation pathway is not sufficient for recruitment to IBs. Finally, we find that reporters and Ub conjugates are stable at IBs. These data indicate that compromised folding states, rather than conjugation to Ub, can specify recruitment to IBs.

scholarly journals Autophagy in Neurodegenerative Diseases: A Hunter for Aggregates

2020 ◽  
Vol 21 (9) ◽  
pp. 3369 ◽  
Author(s):  
Hyungsun Park ◽  
Ju-Hee Kang ◽  
Seongju Lee
Keyword(s):  
Quality Control ◽  
Neurodegenerative Diseases ◽  
Inclusion Bodies ◽  
Amyloid Β ◽  
Control Mechanisms ◽  
Autophagy Induction ◽  
Ubiquitin Proteasome ◽  
Autophagy Pathway ◽  
The Relationship ◽  
Intracellular Inclusion

Cells have developed elaborate quality-control mechanisms for proteins and organelles to maintain cellular homeostasis. Such quality-control mechanisms are maintained by conformational folding via molecular chaperones and by degradation through the ubiquitin-proteasome or autophagy-lysosome system. Accumulating evidence suggests that impaired autophagy contributes to the accumulation of intracellular inclusion bodies consisting of misfolded proteins, which is a hallmark of most neurodegenerative diseases. In addition, genetic mutations in core autophagy-related genes have been reported to be linked to neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Conversely, the pathogenic proteins, such as amyloid β and α-synuclein, are detrimental to the autophagy pathway. Here, we review the recent advances in understanding the relationship between autophagic defects and the pathogenesis of neurodegenerative diseases and suggest autophagy induction as a promising strategy for the treatment of these conditions.

scholarly journals Isoprostanes and Neuroprostanes as Biomarkers of Oxidative Stress in Neurodegenerative Diseases

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Elżbieta Miller ◽  
Agnieszka Morel ◽  
Luciano Saso ◽  
Joanna Saluk
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Neurological Diseases ◽  
The Body ◽  
Jakob Disease ◽  
Novel Biomarkers ◽  
The Relationship ◽  
Biomarkers Of Oxidative Stress

Accumulating data shows that oxidative stress plays a crucial role in neurodegenerative disorders. The literature data indicate thatin vivoor postmortem cerebrospinal fluid and brain tissue levels of F2-isoprostanes (F2-IsoPs) especially F4-neuroprotanes (F4-NPs) are significantly increased in some neurodegenerative diseases: multiple sclerosis, Alzheimer's disease, Huntington's disease, and Creutzfeldt-Jakob disease. Central nervous system is the most metabolically active organ of the body characterized by high requirement for oxygen and relatively low antioxidative activity, what makes neurons and glia highly susceptible to destruction by reactive oxygen/nitrogen species and neurodegeneration. The discovery of F2-IsoPs and F4-NPs as markers of lipid peroxidation caused by the free radicals has opened up new areas of investigation regarding the role of oxidative stress in the pathogenesis of human neurodegenerative diseases. This review focuses on the relationship between F2-IsoPs and F4-NPs as biomarkers of oxidative stress and neurodegenerative diseases. We summarize the knowledge of these novel biomarkers of oxidative stress and the advantages of monitoring their formation to better define the involvement of oxidative stress in neurological diseases.

Mechanisms of disordered neurodegenerative function: concepts and facts about the different roles of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)

2018 ◽  
Vol 29 (4) ◽  
pp. 387-415 ◽  
Author(s):  
Yasmeen M. Taalab ◽  
Nour Ibrahim ◽  
Ahmed Maher ◽  
Mubashir Hassan ◽  
Wael Mohamed ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Kinase ◽  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Protein Misfolding ◽  
Disease Models ◽  
Downstream Signaling ◽  
Unfolded Protein

AbstractNeurodegenerative diseases, such as Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, prion disease, and amyotrophic lateral sclerosis, are a dissimilar group of disorders that share a hallmark feature of accumulation of abnormal intraneuronal or extraneuronal misfolded/unfolded protein and are classified as protein misfolding disorders. Cellular and endoplasmic reticulum (ER) stress activates multiple signaling cascades of the unfolded protein response (UPR). Consequently, translational and transcriptional alterations in target gene expression occur in response directed toward restoring the ER capacity of proteostasis and reestablishing the cellular homeostasis. Evidences fromin vitroandin vivodisease models indicate that disruption of ER homeostasis causes abnormal protein aggregation that leads to synaptic and neuronal dysfunction. However, the exact mechanism by which it contributes to disease progression and pathophysiological changes remains vague. Downstream signaling pathways of UPR are fully integrated, yet with diverse unexpected outcomes in different disease models. Three well-identified ER stress sensors have been implicated in UPR, namely, inositol requiring enzyme 1, protein kinase RNA-activated-like ER kinase (PERK), and activating transcription factor 6. Although it cannot be denied that each of the involved stress sensor initiates a distinct downstream signaling pathway, it becomes increasingly clear that shared pathways are crucial in determining whether or not the UPR will guide the cells toward adaptive prosurvival or proapoptotic responses. We review a body of work on the mechanism of neurodegenerative diseases based on oxidative stress and cell death pathways with emphasis on the role of PERK.

Ultrastructural Correlations between Clonal Human Tumor Colonies and in Vivo Neoplasms

1982 ◽  
Vol 40 ◽  
pp. 210-211
Author(s):  
M.J. Murphy ◽  
R.R. Price ◽  
J.C. Sloman
Keyword(s):  
Cultured Cells ◽  
Human Tumor ◽  
Cell Type ◽  
Tumor Mass ◽  
Initial Cell ◽  
Cloning Assay ◽  
Human Tumor Cloning ◽  
The Relationship

The in vitro human tumor cloning assay originally described by Salmon and Hamburger has been applied recently to the investigation of differential anti-tumor drug sensitivities over a broad range of human neoplasms. A major problem in the acceptance of this technique has been the question of the relationship between the cultured cells and the original patient tumor, i.e., whether the colonies that develop derive from the neoplasm or from some other cell type within the initial cell population. A study of the ultrastructural morphology of the cultured cells vs. patient tumor has therefore been undertaken to resolve this question. Direct correlation was assured by division of a common tumor mass at surgical resection, one biopsy being fixed for TEM studies, the second being rapidly transported to the laboratory for culture.

Do Extra-Platelet Sources Contribute to the Plasma Level of Thrombospondin?

1988 ◽  
Vol 59 (02) ◽  
pp. 273-276 ◽  
Author(s):  
J Dawes ◽  
D A Pratt ◽  
M S Dewar ◽  
F E Preston
Keyword(s):  
Platelet Count ◽  
Background Concentration ◽  
Serum Concentrations ◽  
Bone Marrow Depression ◽  
Serial Sampling ◽  
Control Serum ◽  
Platelet Release ◽  
Highly Correlated ◽  
The Relationship

SummaryThrombospondin, a trimeric glycoprotein contained in the platelet α-granules, has been proposed as a marker of in vivo platelet activation. However, it is also synthesised by a range of other cells. The extraplatelet contribution to plasma levels of thrombospondin was therefore estimated by investigating the relationship between plasma thrombospondin levels and platelet count in samples from profoundly thrombocytopenic patients with marrow hypoplasia, using the platelet-specific α-granule protein β-thromboglobulin as control. Serum concentrations of both proteins were highly correlated with platelet count, but while plasma β-thromboglobulin levels and platelet count also correlated, there was no relationship between the number of platelets and thrombospondin concentrations in plasma. Serial sampling of patients recovering from bone marrow depression indicated that the plasma thrombospondin contributed by platelets is superimposed on a background concentration of at least 50 ng/ml probably derived from a non-platelet source, and plasma thrombospondin levels do not simply reflect platelet release.

Dose Requirement for Replacement Therapy in Hemophilia A

1979 ◽  
Vol 42 (03) ◽  
pp. 825-831 ◽  
Author(s):  
Jean-Pierre Allain
Keyword(s):  
Clinical Effect ◽  
Hemophilia A ◽  
Clinical Results ◽  
Severe Hemophilia ◽  
Dose Requirement ◽  
Viii Level ◽  
The Relationship ◽  
In Vivo Recovery ◽  
Different Doses

SummaryIn order to determine the correlation between different doses of F. VIII and their clinical effect,. 70 children with severe hemophilia A were studied after treatment with single doses of cryoprecipitate. The relationship between plasma F. VIII levels or doses calculated in u/ kg of body weight and clinical results followed an exponential curve. Plasma F. VIII levels of 0.35 and 0.53 u/ml corresponded to 95 and 99% satisfactory treatment, respectively. Similar clinical results were obtained with 20 and 31 u/kg. When the in vivo recovery of F. VIII after lyophilized cryoprecipitate was 0.015 u/ml for each u/kg injected, plasma F. VIII levels of 0.30 and 0.47 u/ml respectively were achieved. Since home treatment is largely based on single infusions of F. VIII, it is suggested that moderate and severe hemorrhages be treated with a dose which will provide a plasma F. VIII level of 0.5 u/ml.

Shall I trust you? From child human-robot interaction to trusting relationships

2019 ◽  
Author(s):  
Cinzia Di Dio ◽  
Federico Manzi ◽  
Giulia Peretti ◽  
Angelo Cangelosi ◽  
Paul L. Harris ◽  
...  
Keyword(s):  
Behavioral Pattern ◽  
Human Robot Interaction ◽  
School Age Children ◽  
Social Relevance ◽  
Robot Interaction ◽  
Cognitive Correlates ◽  
The Social ◽  
The Relationship

Studying trust within human-robot interaction is of great importance given the social relevance of robotic agents in a variety of contexts. We investigated the acquisition, loss and restoration of trust when preschool and school-age children played with either a human or a humanoid robot in-vivo. The relationship between trust and the quality of attachment relationships, Theory of Mind, and executive function skills was also investigated. No differences were found in children’s trust in the play-partner as a function of agency (human or robot). Nevertheless, 3-years-olds showed a trend toward trusting the human more than the robot, while 7-years-olds displayed the reverse behavioral pattern, thus highlighting the developing interplay between affective and cognitive correlates of trust.

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