Advances in gene transfer and pharmacological regulation of protein aggregation in the treatment of Alzheimer’s and parkinson’s diseases

2005 ◽  
pp. 69-80
Author(s):  
P Bar-On ◽  
E Rockenstein ◽  
M Hashimoto ◽  
E Masliah
Keyword(s):  
Gene Transfer ◽  
Protein Aggregation ◽  
Parkinson’S Diseases ◽  
Pharmacological Regulation

Role of Protein Aggregation in Mitochondrial Dysfunction and Neurodegeneration in Alzheimer's and Parkinson's Diseases

2003 ◽  
Vol 4 (1-2) ◽  
pp. 21-36 ◽  
Author(s):  
Makoto Hashimoto ◽  
Edward Rockenstein ◽  
Leslie Crews ◽  
Eliezer Masliah
Keyword(s):  
Protein Aggregation ◽  
Mitochondrial Dysfunction ◽  
Parkinson’S Diseases

scholarly journals The Aggregation of Huntingtin and α-Synuclein

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
María Elena Chánez-Cárdenas ◽  
Edgar Vázquez-Contreras
Keyword(s):  
Protein Aggregation ◽  
Protein Interactions ◽  
Protein Function ◽  
Driving Forces ◽  
Chemical Compounds ◽  
Origin And Evolution ◽  
Parkinson’S Diseases ◽  
Biomaterial Science

Huntington’s and Parkinson’s diseases are neurodegenerative disorders associated with unusual protein interactions. Although the origin and evolution of these diseases are completely different, characteristic deposits of protein aggregates (huntingtin and α-synuclein resp.), are a common feature in both diseases. After these observations, many studies are performed with both proteins. Some of them try to understand the nature and driving forces of the aggregation process; others try to find a correlation between the genetic and failure in protein function. Finally with the combination of both approaches, it was proposed that possible strategies deal with pathologic aggregation. Unfortunately, if protein aggregation is a cause or a consequence of the neurodegeneration observed in these pathologies, it is still debatable. This paper describes the process of aggregation of two proteins: huntingtin and α synuclein. The characteristics of the aggregation reaction of these proteins have been followed with novel methods both in vivo and in vitro; these studies include both the combination with other proteins and the presence of various chemical compounds. The ultimate goal of this study was to summarize recent findings on protein aggregation and its possible role as a therapeutic target in neurodegenerative diseases and their role in biomaterial science.

scholarly journals Bacterial production and direct functional screening of expanded molecular libraries for discovering inhibitors of protein aggregation

2019 ◽  
Vol 5 (10) ◽  
pp. eaax5108 ◽  
Author(s):  
Dafni C. Delivoria ◽  
Sean Chia ◽  
Johnny Habchi ◽  
Michele Perni ◽  
Ilias Matis ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Early Stage ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Functional Screening ◽  
Parkinson’S Diseases ◽  
Aggregation Inhibitors ◽  
Molecular Libraries

Protein misfolding and aggregation are associated with a many human disorders, including Alzheimer’s and Parkinson’s diseases. Toward increasing the effectiveness of early-stage drug discovery for these conditions, we report a bacterial platform that enables the biosynthesis of molecular libraries with expanded diversities and their direct functional screening for discovering protein aggregation inhibitors. We illustrate this approach by performing, what is to our knowledge, the largest functional screen of small-size molecular entities described to date. We generated a combinatorial library of ~200 million drug-like, cyclic peptides and rapidly screened it for aggregation inhibitors against the amyloid-β peptide (Aβ42), linked to Alzheimer’s disease. Through this procedure, we identified more than 400 macrocyclic compounds that efficiently reduce Aβ42 aggregation and toxicity in vitro and in vivo. Finally, we applied a combination of deep sequencing and mutagenesis analyses to demonstrate how this system can rapidly determine structure-activity relationships and define consensus motifs required for bioactivity.

scholarly journals Liquid condensates increase potency of amyloid fibril inhibitors

2020 ◽  
Author(s):  
Thomas C. T. Michaels ◽  
L. Mahadevan ◽  
Christoph A. Weber
Keyword(s):  
Phase Separation ◽  
Protein Aggregation ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Amyloid Formation ◽  
Physiological Processes ◽  
Parkinson’S Diseases ◽  
Spatio Temporal ◽  
Liquid Condensate

In living cells, liquid condensates form in the cytoplasm and nucleoplasm via phase separation and regulate physiological processes. They also regulate aberrant aggregation of amyloid fibrils, a process linked to Alzheimer’s and Parkinson’s diseases. In the absence of condensates it has been shown that amyloid aggregation can be inhibited by molecular chaperones and rationally designed drugs. However it remains unknown how this drug- or chaperone-mediated inhibition of amyloid fibril aggregation is affected by phase-separated condensates. Here we study the interplay between protein aggregation, its inhibition and liquid-liquid phase separation. Our key finding is that the potency of inhibitors of amyloid formation can be strongly enhanced. We show that the corresponding mechanism relies on the colocalization of inhibitors and aggregates inside the liquid condensate. We provide experimentally testable physicochemical conditions under which the increase of inhibitor potency is most pronounced. Our work highlights the role of spatio-temporal heterogeneity in curtailing aberrant protein aggregation and suggests design principles for amyloid inhibitors accounting for partitioning of drugs into liquid condensates.

scholarly journals Inhaled Insulin Forms Toxic Pulmonary Amyloid Aggregates

Endocrinology ◽  
2010 ◽  
Vol 151 (10) ◽  
pp. 4717-4724 ◽  
Author(s):  
Cristian A. Lasagna-Reeves ◽  
Audra L. Clos ◽  
Terumi Midoro-Hiriuti ◽  
Randall M. Goldblum ◽  
George R. Jackson ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Protein Misfolding ◽  
Diabetic Patients ◽  
Amyloid Formation ◽  
Pulmonary Tissue ◽  
Inhaled Insulin ◽  
Parkinson’S Diseases ◽  
Pulmonary Air Flow

It is well known that interfaces, such as polar-nonpolar or liquid-air, play a key role in triggering protein aggregation in vitro, in particular the aggregation of peptides and proteins with the predisposition of misfolding and aggregation. Here we show that the interface present in the lungs predisposes the lungs to form aggregation of inhaled insulin. Insulin inhalers were introduced, and a large number of diabetic patients have used them. Although inhalers were safe and effective, decreases in pulmonary capacity have been reported in response to inhaled insulin. We hypothesize that the lung air-tissue interface provides a template for the aggregation of inhaled insulin. Our studies were designed to investigate the harmful potential that inhaled insulin has in pulmonary tissue in vivo, through an amyloid formation mechanism. Our data demonstrate that inhaled insulin rapidly forms amyloid in the lungs causing a significant reduction in pulmonary air flow. Our studies exemplify the importance that interfaces play in protein aggregation in vivo, illustrating the potential aggregation of inhaled proteins and the formation of amyloid deposits in the lungs. These insulin deposits resemble the amyloid structures implicated in protein misfolding disorders, such as Alzheimer’s and Parkinson’s diseases, and could as well be deleterious in nature.

scholarly journals Protein Aggregation in the Brain: The Molecular Basis for Alzheimer’s and Parkinson’s Diseases

2008 ◽  
Vol 14 (7-8) ◽  
pp. 451-464 ◽  
Author(s):  
G. Brent Irvine ◽  
Omar M. El-Agnaf ◽  
Ganesh M. Shankar ◽  
Dominic M. Walsh
Keyword(s):  
Protein Aggregation ◽  
Molecular Basis ◽  
Parkinson’S Diseases ◽  
The Brain

scholarly journals Optimal control strategies for inhibition of protein aggregation

2019 ◽  
Vol 116 (29) ◽  
pp. 14593-14598 ◽  
Author(s):  
Thomas C. T. Michaels ◽  
Christoph A. Weber ◽  
L. Mahadevan
Keyword(s):  
Protein Aggregation ◽  
Control Strategies ◽  
Model Organism ◽  
Amyloid Β ◽  
Optimal Strategies ◽  
Treatment Protocols ◽  
Medical Disorders ◽  
Molecular Events ◽  
Parkinson’S Diseases ◽  
And Control

Protein aggregation has been implicated in many medical disorders, including Alzheimer’s and Parkinson’s diseases. Potential therapeutic strategies for these diseases propose the use of drugs to inhibit specific molecular events during the aggregation process. However, viable treatment protocols require balancing the efficacy of the drug with its toxicity, while accounting for the underlying events of aggregation and inhibition at the molecular level. To address this key problem, we combine here protein aggregation kinetics and control theory to determine optimal protocols that prevent protein aggregation via specific reaction pathways. We find that the optimal inhibition of primary and fibril-dependent secondary nucleation require fundamentally different drug administration protocols. We test the efficacy of our approach on experimental data for the aggregation of the amyloid-β(1-42) peptide of Alzheimer’s disease in the model organism Caenorhabditis elegans. Our results pose and answer the question of the link between the molecular basis of protein aggregation and optimal strategies for inhibiting it, opening up avenues for the design of rational therapies to control pathological protein aggregation.

Assessment of the Efficacy of Solutes from Extremophiles on Protein Aggregation in Cell Models of Huntington’s and Parkinson’s Diseases

2011 ◽  
Vol 36 (6) ◽  
pp. 1005-1011 ◽  
Author(s):  
Carla D. Jorge ◽  
Rita Ventura ◽  
Christopher Maycock ◽  
Tiago F. Outeiro ◽  
Helena Santos ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Cell Models ◽  
Parkinson’S Diseases

An Ultra-Structural Study of Human Melanoma in Vivo and Vitro

1976 ◽  
Vol 34 ◽  
pp. 258-259
Author(s):  
James R. Gaylor ◽  
Fredda Schafer ◽  
Robert E. Nordquist
Keyword(s):  
Endoplasmic Reticulum ◽  
Golgi Apparatus ◽  
Protein Aggregation ◽  
Structural Study ◽  
Human Melanoma ◽  
Protein Matrix ◽  
Early Form ◽  
Endoplasmic Reticulum Protein ◽  
Mitochondrial Origin

Several theories on the origin of the melanosome exist. These include the Golgi origin theory, in which a tyrosinase-rich protein is "packaged" by the Golgi apparatus, thus forming the early form of the melanosome. A second theory postulates a mitochondrial origin of melanosomes. Its author contends that the melanosome is a modified mitochondria which acquires melanin during its development. A third theory states that a pre-melanosome is formed in the smooth or rough endoplasmic reticulum. Protein aggregation is suggested by one author as a possible source of the melanosome. This fourth theory postulates that the melanosome originates when the protein products of several genetic loci aggregate in the cytoplasm of the melanocyte. It is this protein matrix on which the melanin is deposited. It was with these theories in mind that this project was undertaken.

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