Protein Aggregation and Pathogenesis of Huntingtons Disease: Mechanisms and Correlations

2000 ◽  
Vol 381 (9-10) ◽  
pp. 937-942 ◽  
Author(s):  
Erich E. Wanker
Keyword(s):  
Protein Aggregation ◽  
Disease Progression ◽  
Late Onset ◽  
Muscular Atrophy ◽  
Model Systems ◽  
Glutamine Repeat ◽  
Characteristic Features ◽  
Spinal Bulbar Muscular Atrophy

Abstract The formation of insoluble protein aggregates is a hallmark of Huntington's disease (HD) and related neurodegenerative disorders, such as dentatorubral pallidoluysian atrophy (DRPLA), spinal bulbar muscular atrophy (SBMA) and the spinocerebellar ataxia (SCA) type 1, 2, 3, 6 and 7. These disorders are caused by an expanded polyglutamine (polyQ) tract in otherwise unrelated proteins. They are characterized by late-onset, selective neuropathology, a pathogenic polyQ threshold and a relationship between polyQ length and disease progression. Thus, molecular models of HD and related glutamine-repeat disorders must account for these characteristic features. During the last three years, considerable effort has been invested in the development of in vitro and in vivo model systems to study the mechanisms of protein aggregation in glutamine-repeat disorders and its potential effects on disease progression and neurodegeneration. A selection of these studies is reviewed here. Furthermore, the correlation between aggregate formation and development of HD is discussed.

scholarly journals Dynamics of a Protein Interaction Network Associated to the Aggregation of polyQ-Expanded Ataxin-1

Genes ◽  
2020 ◽  
Vol 11 (10) ◽  
pp. 1129
Author(s):  
Aimilia-Christina Vagiona ◽  
Miguel A. Andrade-Navarro ◽  
Fotis Psomopoulos ◽  
Spyros Petrakis
Keyword(s):  
Animal Models ◽  
Protein Aggregation ◽  
Disease Progression ◽  
Protein Interaction ◽  
Molecular Mechanisms ◽  
Spinocerebellar Ataxia Type ◽  
In Vivo Model ◽  
Ppi Networks

Background: Several experimental models of polyglutamine (polyQ) diseases have been previously developed that are useful for studying disease progression in the primarily affected central nervous system. However, there is a missing link between cellular and animal models that would indicate the molecular defects occurring in neurons and are responsible for the disease phenotype in vivo. Methods: Here, we used a computational approach to identify dysregulated pathways shared by an in vitro and an in vivo model of ATXN1(Q82) protein aggregation, the mutant protein that causes the neurodegenerative polyQ disease spinocerebellar ataxia type-1 (SCA1). Results: A set of common dysregulated pathways were identified, which were utilized to construct cerebellum-specific protein-protein interaction (PPI) networks at various time-points of protein aggregation. Analysis of a SCA1 network indicated important nodes which regulate its function and might represent potential pharmacological targets. Furthermore, a set of drugs interacting with these nodes and predicted to enter the blood–brain barrier (BBB) was identified. Conclusions: Our study points to molecular mechanisms of SCA1 linked from both cellular and animal models and suggests drugs that could be tested to determine whether they affect the aggregation of pathogenic ATXN1 and SCA1 disease progression.

scholarly journals Huntington's disease: from gene to potential therapy

2001 ◽  
Vol 3 (1) ◽  
pp. 17-23
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Western Europe ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Cell Metabolism ◽  
Normal Function ◽  
Model Systems

Huntington's disease (HD) is a progressive, late-onset neurodegenerative illness with autosomal dominant inheritance that affects one in 10 000 individuals in Western Europe. The disease is caused by a polyglutamine repeat expansion located in the N-terminal region of the huntingtin protein. The mutation is likely to act by a gain of function, but the molecular mechanisms by which it leads to neuronal dysfunction and cell death are not yet known. The normal function of huntingtin in cell metabolism is also unclear. There is no therapy for HD. Research on HD should help elucidate the pathogenetic mechanism of this illness in order to develop successful treatments to prevent or slow down symptoms. This article presents new results in HD research focusing on in vivo and in vitro model systems, potential molecular mechanisms of HD, and the development of therapeutic strategies.

scholarly journals Kinetic analysis reveals the rates and mechanisms of protein aggregation in a multicellular organism

2020 ◽  
Author(s):  
Tessa Sinnige ◽  
Georg Meisl ◽  
Thomas C. T. Michaels ◽  
Michele Vendruscolo ◽  
Tuomas P.J. Knowles ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Protein Misfolding ◽  
Molecular Model ◽  
Kinetic Studies ◽  
Living Organism ◽  
Model Systems ◽  
Amyloid Formation ◽  
Wide Range

AbstractThe accumulation of insoluble protein aggregates containing amyloid fibrils has been observed in many different human protein misfolding diseases1,2, and their pathological features have been recapitulated in diverse model systems3. In vitro kinetic studies have provided a quantitative understanding of how the fundamental molecular level processes of nucleation and growth lead to amyloid formation4. However, it is not yet clear to what extent these basic biophysical processes translate to amyloid formation in vivo, given the complexity of the cellular and organismal environment. Here we show that the aggregation of a fluorescently tagged polyglutamine (polyQ) protein into µm-sized inclusions in the muscle tissue of living C. elegans can be quantitatively described by a molecular model where stochastic nucleation occurs independently in each cell, followed by rapid aggregate growth. Global fitting of the image-based aggregation kinetics reveals a nucleation rate corresponding to 0.01 h-1 per cell at 1 mM intracellular protein concentration, and shows that the intrinsic stochasticity of nucleation accounts for a significant fraction of the observed animal-to-animal variation. Our results are consistent with observations for the aggregation of polyQ proteins in vitro5 and in cell culture6, and highlight how nucleation events control the overall progression of aggregation in the organism through the spatial confinement into individual cells. The key finding that the biophysical principles associated with protein aggregation in small volumes remain the governing factors, even in the complex environment of a living organism, will be critical for the interpretation of in vivo data from a wide range of protein aggregation diseases.

scholarly journals Genetic Suppressor Element 1 (GSE1) Promotes the Oncogenic and Recurrent Phenotypes of Castration-Resistant Prostate Cancer by Targeting Tumor-Associated Calcium Signal Transducer 2 (TACSTD2)

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3959
Author(s):  
Oluwaseun Adebayo Bamodu ◽  
Yuan-Hung Wang ◽  
Chen-Hsun Ho ◽  
Su-Wei Hu ◽  
Chia-Da Lin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Therapy Resistance ◽  
Calcium Signal ◽  
Signal Transducer ◽  
Castration Resistance ◽  
Castration Resistant

Background: prostate cancer (PCa) is a principal cause of cancer-related morbidity and mortality. Castration resistance and metastasis are clinical challenges and continue to impede therapeutic success, despite diagnostic and therapeutic advances. There are reports of the oncogenic activity of genetic suppressor element (GSE)1 in breast and gastric cancers; however, its role in therapy resistance, metastasis, and susceptibility to disease recurrence in PCa patients remains unclear. Objective: this study investigated the role of aberrantly expressed GSE1 in the metastasis, therapy resistance, relapse, and poor prognosis of advanced PCa. Methods: we used a large cohort of multi-omics data and in vitro, ex vivo, and in vivo assays to investigate the potential effect of altered GSE1 expression on advanced/castration-resistant PCa (CRPC) treatment responses, disease progression, and prognosis. Results: using a multi-cohort approach, we showed that GSE1 is upregulated in PCa, while tumor-associated calcium signal transducer 2 (TACSTD2) is downregulated. Moreover, the direct, but inverse, correlation interaction between GSE1 and TACSTD2 drives metastatic disease, castration resistance, and disease progression and modulates the clinical and immune statuses of patients with PCa. Patients with GSE1highTACSTD2low expression are more prone to recurrence and disease-specific death than their GSE1lowTACSTD2high counterparts. Interestingly, we found that the GSE1–TACSTD2 expression profile is associated with the therapy responses and clinical outcomes in patients with PCa, especially those with metastatic/recurrent disease. Furthermore, we demonstrate that the shRNA-mediated targeting of GSE1 (shGSE1) significantly inhibits cell proliferation and attenuates cell migration and tumorsphere formation in metastatic PC3 and DU145 cell lines, with an associated suppression of VIM, SNAI2, and BCL2 and the concomitant upregulation of TACSTD2 and BAX. Moreover, shGSE1 enhances sensitivity to the antiandrogens abiraterone and enzalutamide in vitro and in vivo. Conclusion: these data provide preclinical evidence of the oncogenic role of dysregulated GSE1–TACSTD2 signaling and show that the molecular or pharmacological targeting of GSE1 is a workable therapeutic strategy for inhibiting androgen-driven oncogenic signals, re-sensitizing CRPC to treatment, and repressing the metastatic/recurrent phenotypes of patients with PCa.

In Vitro and In Vivo Model Systems for the Study of Allergic and Inflammatory Disorders in Man

CHEST Journal ◽  
1985 ◽  
Vol 87 (5) ◽  
pp. 162S-164S ◽  
Author(s):  
Stephen P. Peters ◽  
Robert M. Naclerio ◽  
Alkis Togias ◽  
Robert P. Schleimer ◽  
Donald W. MacGlashan ◽  
...  
Keyword(s):  
Model Systems ◽  
In Vivo Model ◽  
Inflammatory Disorders

376 A phase I/II study of live biotherapeutic MRx0518 in combination with pembrolizumab in patients refractory to immune checkpoint inhibitors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A401-A401
Author(s):  
Shubham Pant ◽  
Amishi Shah ◽  
Pavlos Msaouel ◽  
Matthew Campbell ◽  
Shi-Ming Tu ◽  
...  
Keyword(s):  
Phase I ◽  
Disease Progression ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumour Response ◽  
Checkpoint Inhibition ◽  
Single Strain

BackgroundMRx0518 is a novel, human gut microbiome-derived, single-strain, oral live biotherapeutic. It is a bacterium of the Enterococcus genus that was selected for development in the treatment of solid tumours for its strong in vitro and in vivo immunostimulatory activity. In vivo studies have shown that MRx0518 can inhibit tumour growth in different syngeneic cancer models as monotherapy and in combination with checkpoint inhibitors. MRx0518 has been shown to reduce Treg and increase Th1 and Tc1 lymphocyte differentiation in vitro, and increase intratumoral CD4+ and CD8+ T cells and NK cells in vivo.This phase I/II clinical study is evaluating the combination of MRx0518 and pembrolizumab in a cohort of heavily pre-treated patients refractory to immune checkpoint inhibitors (ICIs) to assess whether it is safe and can provide a clinical benefit.MethodsThe study is being conducted in two parts. Part A is complete and evaluated safety of the combination therapy in a cohort of 12 mRCC and mNSCLC patients. This data was assessed by the Safety Review Committee and it was determined appropriate to proceed to Part B. Part B is now recruiting up to 30 additional patients per indication (RCC, NSCLC or bladder cancer) at several US sites. Patients in both parts must be refractory to checkpoint inhibition. This is defined as having had an initial benefit from PD-1 pathway targeting immune checkpoint inhibition (ICI) but developing disease progression confirmed by two radiological scans ≥4 weeks apart in the absence of rapid clinical progression and within 12 weeks of last dose of ICI. Patients are treated with 1 capsule of MRx0518 (1 × 1010 to 1 × 1011 CFU) twice daily and pembrolizumab (200 mg every 3 weeks) for up to 35 cycles or until disease progression. Tumour response is assessed every 9 weeks per RECIST. Blood, stool and urine samples are collected throughout the study to evaluate immune markers and microbiome. Patients may choose to consent to tissue biopsies. The primary objective of the study is to evaluate safety of the combination by monitoring toxicities in the first cycle of treatment. Secondary objectives are to evaluate efficacy via ORR, DOR, DCR (CR, PR or SD ≥6 months) and PFS. Exploratory objectives are to evaluate biomarkers of treatment effect, impact on microbiota and OS and correlation of clinical outcome with PD-L1 CPS/TPS.ResultsN/AConclusionsN/ATrial RegistrationNCT03637803Ethics ApprovalThis study was approved by University of Texas MD Anderson’s Institutional Review Board; approval ref. 2018-0290

scholarly journals Role of SHH in Patterning Human Pluripotent Cells towards Ventral Forebrain Fates

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 914
Author(s):  
Melanie V. Brady ◽  
Flora M. Vaccarino
Keyword(s):  
Stem Cell ◽  
Human Brain ◽  
Human Development ◽  
Disease Modeling ◽  
Model Systems ◽  
Advantages And Disadvantages ◽  
Technical Ability ◽  
Cellular Phenotypes

The complexities of human neurodevelopment have historically been challenging to decipher but continue to be of great interest in the contexts of healthy neurobiology and disease. The classic animal models and monolayer in vitro systems have limited the types of questions scientists can strive to answer in addition to the technical ability to answer them. However, the tridimensional human stem cell-derived organoid system provides the unique opportunity to model human development and mimic the diverse cellular composition of human organs. This strategy is adaptable and malleable, and these neural organoids possess the morphogenic sensitivity to be patterned in various ways to generate the different regions of the human brain. Furthermore, recapitulating human development provides a platform for disease modeling. One master regulator of human neurodevelopment in many regions of the human brain is sonic hedgehog (SHH), whose expression gradient and pathway activation are responsible for conferring ventral identity and shaping cellular phenotypes throughout the neural axis. This review first discusses the benefits, challenges, and limitations of using organoids for studying human neurodevelopment and disease, comparing advantages and disadvantages with other in vivo and in vitro model systems. Next, we explore the range of control that SHH exhibits on human neurodevelopment, and the application of SHH to various stem cell methodologies, including organoids, to expand our understanding of human development and disease. We outline how this strategy will eventually bring us much closer to uncovering the intricacies of human neurodevelopment and biology.

scholarly journals Considerations to Model Heart Disease in Women with Preeclampsia and Cardiovascular Disease

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 899
Author(s):  
Clara Liu Chung Ming ◽  
Kimberly Sesperez ◽  
Eitan Ben-Sefer ◽  
David Arpon ◽  
Kristine McGrath ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
Ex Vivo ◽  
Myocardial Damage ◽  
Cardiovascular Disorder ◽  
Model Systems ◽  
Ex Vivo Model ◽  
Disease Manifestation

Preeclampsia is a multifactorial cardiovascular disorder diagnosed after 20 weeks of gestation, and is the leading cause of death for both mothers and babies in pregnancy. The pathophysiology remains poorly understood due to the variability and unpredictability of disease manifestation when studied in animal models. After preeclampsia, both mothers and offspring have a higher risk of cardiovascular disease (CVD), including myocardial infarction or heart attack and heart failure (HF). Myocardial infarction is an acute myocardial damage that can be treated through reperfusion; however, this therapeutic approach leads to ischemic/reperfusion injury (IRI), often leading to HF. In this review, we compared the current in vivo, in vitro and ex vivo model systems used to study preeclampsia, IRI and HF. Future studies aiming at evaluating CVD in preeclampsia patients could benefit from novel models that better mimic the complex scenario described in this article.

scholarly journals The Effect of Oxidized Dopamine on the Structure and Molecular Chaperone Function of the Small Heat-Shock Proteins, αB-Crystallin and Hsp27

2021 ◽  
Vol 22 (7) ◽  
pp. 3700
Author(s):  
Junna Hayashi ◽  
Jennifer Ton ◽  
Sparsh Negi ◽  
Daniel E. K. M. Stephens ◽  
Dean L. Pountney ◽  
...  
Keyword(s):  
Heat Shock ◽  
Protein Aggregation ◽  
Molecular Chaperone ◽  
Cross Linking ◽  
Αb Crystallin ◽  
The Cross ◽  
Shock Proteins ◽  
And Function

Oxidation of the neurotransmitter, dopamine (DA), is a pathological hallmark of Parkinson’s disease (PD). Oxidized DA forms adducts with proteins which can alter their functionality. αB-crystallin and Hsp27 are intracellular, small heat-shock molecular chaperone proteins (sHsps) which form the first line of defense to prevent protein aggregation under conditions of cellular stress. In vitro, the effects of oxidized DA on the structure and function of αB-crystallin and Hsp27 were investigated. Oxidized DA promoted the cross-linking of αB-crystallin and Hsp27 to form well-defined dimer, trimer, tetramer, etc., species, as monitored by SDS-PAGE. Lysine residues were involved in the cross-links. The secondary structure of the sHsps was not altered significantly upon cross-linking with oxidized DA but their oligomeric size was increased. When modified with a molar equivalent of DA, sHsp chaperone functionality was largely retained in preventing both amorphous and amyloid fibrillar aggregation, including fibril formation of mutant (A53T) α-synuclein, a protein whose aggregation is associated with autosomal PD. In the main, higher levels of sHsp modification with DA led to a reduction in chaperone effectiveness. In vivo, DA is sequestered into acidic vesicles to prevent its oxidation and, intracellularly, oxidation is minimized by mM levels of the antioxidant, glutathione. In vitro, acidic pH and glutathione prevented the formation of oxidized DA-induced cross-linking of the sHsps. Oxidized DA-modified αB-crystallin and Hsp27 were not cytotoxic. In a cellular context, retention of significant chaperone functionality by mildly oxidized DA-modified sHsps would contribute to proteostasis by preventing protein aggregation (particularly of α-synuclein) that is associated with PD.

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