scholarly journals The Role of Vesicle Trafficking Defects in the Pathogenesis of Prion and Prion-Like Disorders

2020 ◽  
Vol 21 (19) ◽  
pp. 7016
Author(s):  
Pearl Cherry ◽  
Sabine Gilch
Keyword(s):  
Neurodegenerative Diseases ◽  
Prion Diseases ◽  
Primary Component ◽  
Vesicular Trafficking ◽  
Polyglutamine Diseases ◽  
Amyloid Aggregates ◽  
The Common ◽  
Trafficking Defects ◽  
Insight Into

Prion diseases are fatal and transmissible neurodegenerative diseases in which the cellular form of the prion protein ‘PrPc’, misfolds into an infectious and aggregation prone isoform termed PrPSc, which is the primary component of prions. Many neurodegenerative diseases, like Alzheimer’s disease, Parkinson’s disease, and polyglutamine diseases, such as Huntington’s disease, are considered prion-like disorders because of the common characteristics in the propagation and spreading of misfolded proteins that they share with the prion diseases. Unlike prion diseases, these are non-infectious outside experimental settings. Many vesicular trafficking impairments, which are observed in prion and prion-like disorders, favor the accumulation of the pathogenic amyloid aggregates. In addition, many of the vesicular trafficking impairments that arise in these diseases, turn out to be further aggravating factors. This review offers an insight into the currently known vesicular trafficking defects in these neurodegenerative diseases and their implications on disease progression. These findings suggest that these impaired trafficking pathways may represent similar therapeutic targets in these classes of neurodegenerative disorders.

scholarly journals Thermodynamics of Homopeptide Aggregation

2020 ◽  
Author(s):  
Tam T. M. Phan ◽  
Jeremy D. Schmit
Keyword(s):  
Neurodegenerative Diseases ◽  
Disease Progression ◽  
Prion Diseases ◽  
Steric Repulsion ◽  
Polymer Micelles ◽  
Amyloid Aggregates ◽  
Exon 1 ◽  
Flanking Sequences ◽  
Precise Role

ABSTRACTAmyloid aggregates are found in many neurodegenerative diseases including Huntington’s, Alzheimer’s, and prion diseases. The precise role of the aggregates in disease progression has been difficult to elucidate due to the diversity of aggregated states they can adopt. Here we study the formation of fibrils and oligomers by exon 1 of huntingtin protein. We show that the oligomer states are consistent with polymer micelles that are limited in size by the stretching entropy of the polyglutamine region. The model shows how the sequences flanking the amyloid core modulate aggregation behavior. The N17 region promotes aggregation through weakly attractive interactions, while the C38 tail opposes aggregation via steric repulsion. We also show that the energetics of cross-β stacking by polyglutamine would produce fibrils with many alignment defects, but minor perturbations from the flanking sequences are sufficient to reduce the defects to the level observed in experiment. We conclude with a discussion of the implications of this model for other amyloid forming molecules.

Role of the Structural Characteristics of Dendrimers in the Manifestation of the Antiamyloid Properties

INEOS OPEN ◽  
2020 ◽  
Vol 3 ◽  
Author(s):  
S. A. Sorokina ◽  
◽  
Yu. Yu. Stroilova ◽  
V. I. Muronets ◽  
Z. B. Shifrina ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Structural Characteristics ◽  
Short Review ◽  
External Factors ◽  
Amyloid Aggregation ◽  
Amyloid Proteins ◽  
Molecular Parameters ◽  
Amyloid Aggregates ◽  
Aggregation Processes

Among the compounds able to efficiently inhibit the amyloid aggregation of proteins and decompose the amyloid aggregates that cause neurodegenerative diseases, of particular interest are dendrimers, which represent individual macromolecules with the hypercrosslinked architectures and given molecular parameters. This short review outlines the peculiarities of the antiamyloid activity of dendrimers and discusses the effect of dendrimer structures and external factors on their antiamyloid properties. The potential of application of dendrimers in further investigations on the aggregation processes of amyloid proteins as the compounds that exhibit the remarkable antiamyloid activity is evaluated.

scholarly journals The Effect of Octapeptide Repeats on Prion Folding and Misfolding

2021 ◽  
Vol 22 (4) ◽  
pp. 1800
Author(s):  
Kun-Hua Yu ◽  
Mei-Yu Huang ◽  
Yi-Ru Lee ◽  
Yu-Kie Lin ◽  
Hau-Ren Chen ◽  
...  
Keyword(s):  
Amyloid Fibrils ◽  
Age Of Onset ◽  
Prion Diseases ◽  
Critical Role ◽  
Threshold Effect ◽  
Central Feature ◽  
Terminal Domain ◽  
Amyloid Aggregates

Misfolding of prion protein (PrP) into amyloid aggregates is the central feature of prion diseases. PrP has an amyloidogenic C-terminal domain with three α-helices and a flexible tail in the N-terminal domain in which multiple octapeptide repeats are present in most mammals. The role of the octapeptides in prion diseases has previously been underestimated because the octapeptides are not located in the amyloidogenic domain. Correlation between the number of octapeptide repeats and age of onset suggests the critical role of octapeptide repeats in prion diseases. In this study, we have investigated four PrP variants without any octapeptides and with 1, 5 and 8 octapeptide repeats. From the comparison of the protein structure and the thermal stability of these proteins, as well as the characterization of amyloids converted from these PrP variants, we found that octapeptide repeats affect both folding and misfolding of PrP creating amyloid fibrils with distinct structures. Deletion of octapeptides forms fewer twisted fibrils and weakens the cytotoxicity. Insertion of octapeptides enhances the formation of typical silk-like fibrils but it does not increase the cytotoxicity. There might be some threshold effect and increasing the number of peptides beyond a certain limit has no further effect on the cell viability, though the reasons are unclear at this stage. Overall, the results of this study elucidate the molecular mechanism of octapeptides at the onset of prion diseases.

Prionopathies and Prionlike Protein Aberrations in Neurodegenerative Diseases

Neurographics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 127-148
Author(s):  
K.N. Anderson ◽  
W.B. Overcast ◽  
J.R. Brosch ◽  
B.D. Graner ◽  
M.C. Veronesi
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Clinical Presentation ◽  
Prion Diseases ◽  
Imaging Biomarkers ◽  
Amyloid Pet ◽  
Imaging Features ◽  
Jakob Disease ◽  
The Common ◽  
Neuro Imaging

Protein misfolding has been an area of intense research and is implicated in a number of neurodegenerative diseases. Key proteins in the brain lose their native ability to fold and instead assume abnormal conformations. Misfolded proteins cluster to form pathologic aggregates, which cause cellular dysfunction, neuronal death, and neurodegeneration. The prionopathies are best known among the neurodegenerative diseases for their ability to misfold, self-propagate, and infect other organisms. There is increasing evidence of a rationale for a prionlike mechanism of spread of other neurodegenerative diseases through a similar seeding mechanism. In this review, we detail the role of a key protein aberration known to the various prion diseases, including sporadic, variant, and iatrogenic Creutzfeldt-Jakob disease; variably protease-sensitive prionopathy; Gerstmann-Straussler-Scheinker disease; fatal familial insomnia; and kuru. We also discuss the clinical presentation, the available, and emerging imaging options for these diseases. In the second part of this review, we delineate how a prionlike seeding process may be driving the progression of other neurodegenerative diseases, including Parkinson disease, Alzheimer disease, and Huntington disease. A discussion of clinical presentation and imaging features of these example diseases follows to make a case for a common approach to developing imaging biomarkers and therapies of these diseases.Learning Objective: Upon completion of this article, one should be able to describe the various types of prion diseases, recognize and identify the common the neuro-imaging findings in prion diseases, describe seeding mechanism of prion disease, list the common amyloid PET tracers used for Alzheimer’s disease, and list common imaging biomarkers in neurodegenerative diseases.

scholarly journals De Novo designed 13 mer hairpin-peptide arrests insulin and inhibits its aggregation: role of OH–π interactions between water and hydrophobic amino acids

RSC Advances ◽  
2020 ◽  
Vol 10 (25) ◽  
pp. 14991-14999
Author(s):  
Meghomukta Mukherjee ◽  
Nilanjan Banerjee ◽  
Subhrangsu Chatterjee
Keyword(s):  
Amino Acids ◽  
Neurodegenerative Diseases ◽  
Type Ii Diabetes ◽  
De Novo ◽  
Prion Diseases ◽  
Cellular Systems ◽  
Type Ii ◽  
P Protein ◽  
Hydrophobic Amino Acids

Protein aggregation in the cellular systems can be highly fatal causing a series of diseases including neurodegenerative diseases like ALS, Alzheimer, Prion Diseases, Parkinson's and other diseases like type II diabetes.

scholarly journals MicroRNAs: a complex regulatory network drives the acquisition of malignant cell phenotype

2010 ◽  
Vol 17 (1) ◽  
pp. F51-F75 ◽  
Author(s):  
Libero Santarpia ◽  
Milena Nicoloso ◽  
George A Calin
Keyword(s):  
Cancer Biology ◽  
Malignant Cell ◽  
Cell Phenotype ◽  
Endocrine Tumors ◽  
Functional Capabilities ◽  
Self Sufficiency ◽  
Multistep Process ◽  
The Common ◽  
Insight Into

Several lines of evidence indicate that tumorigenesis is a complex multistep process, and that most, if not all, cancers acquire the same set of functional capabilities during development and progression, albeit through various mechanistic strategies. Increasing data show an important role of microRNAs (miRNAs or miRs) in regulating various aspects of cancer biology. This review describes the role of microRNAs during the multiple steps that drive the progressive transformation of normal cells into highly malignant derivatives, outlining the role of microRNAs in regulating the common hallmarks of tumorigenesis: self-sufficiency in growth signals, insensitivity to antigrowth signals, abnormal apoptosis, limitless replicative potential, induction and sustained angiogenesis, and tissue invasion and metastasis. Recent evidence suggests an important role of microRNAs in the regulation of the expression of most genes regulating and coordinating a wide variety of processes in endocrine glands. We will highlight microRNAs of potential relevance to endocrine tumors and hormone-dependent cancers. Through this overview of how microRNAs regulate multiple targets and entire pathways, we will provide insight into the potential to develop new molecular microRNA-targeted therapies for endocrine tumors.

scholarly journals Exosomes: Innocent Bystanders or Critical Culprits in Neurodegenerative Diseases

2021 ◽  
Vol 9 ◽  
Author(s):  
Margarida Beatriz ◽  
Rita Vilaça ◽  
Carla Lopes
Keyword(s):  
Neurodegenerative Diseases ◽  
Intercellular Communication ◽  
Prion Diseases ◽  
Genetic Material ◽  
Cell Communication ◽  
Protein Aggregates ◽  
Potential Benefits ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Extracellular vesicles (EVs) are nano-sized membrane-enclosed particles released by cells that participate in intercellular communication through the transfer of biologic material. EVs include exosomes that are small vesicles that were initially associated with the disposal of cellular garbage; however, recent findings point toward a function as natural carriers of a wide variety of genetic material and proteins. Indeed, exosomes are vesicle mediators of intercellular communication and maintenance of cellular homeostasis. The role of exosomes in health and age-associated diseases is far from being understood, but recent evidence implicates exosomes as causative players in the spread of neurodegenerative diseases. Cells from the central nervous system (CNS) use exosomes as a strategy not only to eliminate membranes, toxic proteins, and RNA species but also to mediate short and long cell-to-cell communication as carriers of important messengers and signals. The accumulation of protein aggregates is a common pathological hallmark in many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and prion diseases. Protein aggregates can be removed and delivered to degradation by the endo-lysosomal pathway or can be incorporated in multivesicular bodies (MVBs) that are further released to the extracellular space as exosomes. Because exosome transport damaged cellular material, this eventually contributes to the spread of pathological misfolded proteins within the brain, thus promoting the neurodegeneration process. In this review, we focus on the role of exosomes in CNS homeostasis, their possible contribution to the development of neurodegenerative diseases, the usefulness of exosome cargo as biomarkers of disease, and the potential benefits of plasma circulating CNS-derived exosomes.

Sign in / Sign up

Export Citation Format

Share Document