scholarly journals Emerging Roles of Functional Bacterial Amyloids in Gene Regulation, Toxicity, and Immunomodulation

2020 ◽  
Vol 85 (1) ◽  
Author(s):  
Nir Salinas ◽  
Tatyana L. Povolotsky ◽  
Meytal Landau ◽  
Ilana Kolodkin-Gal
Keyword(s):  
Extracellular Matrix ◽  
Gene Regulation ◽  
Neurodegenerative Diseases ◽  
Protein Aggregates ◽  
Microbial Physiology ◽  
Amyloid Fibers

Bacteria often reside in multicellular communities, called biofilms, held together by an extracellular matrix. In many bacteria, the major proteinaceous component of the biofilm are amyloid fibers. Amyloids are highly stable and structured protein aggregates which were known mostly to be associated with neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. In recent years, microbial amyloids were identified also in other species and shown to play major roles in microbial physiology and virulence.

scholarly journals Nanomechanical properties of steric zipper globular structures

2019 ◽  
Vol 116 (45) ◽  
pp. 22478-22484
Author(s):  
Neta Lester-Zer ◽  
Mnar Ghrayeb ◽  
Liraz Chai
Keyword(s):  
Extracellular Matrix ◽  
Neurodegenerative Diseases ◽  
Functional Role ◽  
Crystallographic Structure ◽  
Characteristic Parameters ◽  
Amyloid Fibers ◽  
Nanomechanical Properties ◽  
Atomic Force ◽  
High Propensity ◽  
Bacteria And Fungi

The term amyloid defines a group of proteins that aggregate into plaques or fibers. Amyloid fibers gained their fame mostly due to their relation with neurodegenerative diseases in humans. However, secreted by lower organisms, such as bacteria and fungi, amyloid fibers play a functional role: for example, when they serve as cement in the extracellular matrix of biofilms. Originating either in humans or in microorganisms, the sequence of amyloid proteins is decorated with hexapeptides with high propensity to form fibers, known as steric zippers. We have found that steric zippers form globular structures on route to making fibers and exhibit a characteristic force–distance (F-D) fingerprint when pulled with an atomic force microscope (AFM) tip. Particularly, the F-D pulling curves showed force plateau steps, suggesting that the globular structures were composed of chains that were unwound like a yarn ball. Force plateau analysis showed that the F-D characteristic parameters were sequence sensitive, representing differences in the packing of the hexapeptides within the globules. These unprecedented findings show that steric zippers exhibit a characteristic nanomechanical signature in solution in addition to previously observed characteristic crystallographic structure. Getting to the fundamental interactions that govern the unzipping of full-length amyloid fibers may initiate the development of antiamyloid methods that target the physical in addition to the structural properties of steric zippers.

Extracellular Matrix Dependent Gene Regulation in Mammary Epithelial Cells

1995 ◽  
pp. 107-119 ◽  
Author(s):  
Christian Schmidhauser ◽  
Connie A. Myers ◽  
Romina Mossi ◽  
Gerald F. Casperson ◽  
Mina J. Bissell
Keyword(s):  
Extracellular Matrix ◽  
Gene Regulation ◽  
Epithelial Cells ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial

scholarly journals Amitriptyline interferes with autophagy-mediated clearance of protein aggregates via inhibiting autophagosome maturation in neuronal cells

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Yoonjung Kwon ◽  
Yeojin Bang ◽  
Soung-Hee Moon ◽  
Aeri Kim ◽  
Hyun Jin Choi
Keyword(s):  
Neurodegenerative Diseases ◽  
Depressive Disorders ◽  
Neuronal Cells ◽  
Protein Aggregates ◽  
Underlying Mechanism ◽  
Tricyclic Antidepressant ◽  
Autophagic Flux ◽  
Autophagosome Maturation

Abstract Amitriptyline is a tricyclic antidepressant commonly prescribed for major depressive disorders, as well as depressive symptoms associated with various neurological disorders. A possible correlation between the use of tricyclic antidepressants and the occurrence of Parkinson’s disease has been reported, but its underlying mechanism remains unknown. The accumulation of misfolded protein aggregates has been suggested to cause cellular toxicity and has been implicated in the common pathogenesis of neurodegenerative diseases. Here, we examined the effect of amitriptyline on protein clearance and its relevant mechanisms in neuronal cells. Amitriptyline exacerbated the accumulation of abnormal aggregates in both in vitro neuronal cells and in vivo mice brain by interfering with the (1) formation of aggresome-like aggregates and (2) autophagy-mediated clearance of aggregates. Amitriptyline upregulated LC3B-II, but LC3B-II levels did not increase further in the presence of NH4Cl, which suggests that amitriptyline inhibited autophagic flux rather than autophagy induction. Amitriptyline interfered with the fusion of autophagosome and lysosome through the activation of PI3K/Akt/mTOR pathway and Beclin 1 acetylation, and regulated lysosome positioning by increasing the interaction between proteins Arl8, SKIP, and kinesin. To the best of our knowledge, we are the first to demonstrate that amitriptyline interferes with autophagic flux by regulating the autophagosome maturation during autophagy in neuronal cells. The present study could provide neurobiological clue for the possible correlation between the amitriptyline use and the risk of developing neurodegenerative diseases.

scholarly journals Protein Targets of Oxidative Damage in Human Neurodegenerative Diseases with Abnormal Protein Aggregates

2010 ◽  
Vol 20 (2) ◽  
pp. 281-297 ◽  
Author(s):  
Anna Martínez ◽  
Manuel Portero-Otin ◽  
Reinald Pamplona ◽  
Isidre Ferrer
Keyword(s):  
Oxidative Damage ◽  
Neurodegenerative Diseases ◽  
Protein Aggregates ◽  
Protein Targets ◽  
Abnormal Protein

scholarly journals Transcellular spreading of huntingtin aggregates in the Drosophila brain

2015 ◽  
Vol 112 (39) ◽  
pp. E5427-E5433 ◽  
Author(s):  
Daniel T. Babcock ◽  
Barry Ganetzky
Keyword(s):  
Fusion Protein ◽  
Neurodegenerative Diseases ◽  
Disease Progression ◽  
Protein Aggregates ◽  
Misfolded Proteins ◽  
Drosophila Brain ◽  
Active Release ◽  
Fluorescent Tag ◽  
The Brain ◽  
Expanded Form

A key feature of many neurodegenerative diseases is the accumulation and subsequent aggregation of misfolded proteins. Recent studies have highlighted the transcellular propagation of protein aggregates in several major neurodegenerative diseases, although the precise mechanisms underlying this spreading and how it relates to disease pathology remain unclear. Here we use a polyglutamine-expanded form of human huntingtin (Htt) with a fluorescent tag to monitor the spreading of aggregates in the Drosophila brain in a model of Huntington’s disease. Upon expression of this construct in a defined subset of neurons, we demonstrate that protein aggregates accumulate at synaptic terminals and progressively spread throughout the brain. These aggregates are internalized and accumulate within other neurons. We show that Htt aggregates cause non–cell-autonomous pathology, including loss of vulnerable neurons that can be prevented by inhibiting endocytosis in these neurons. Finally we show that the release of aggregates requires N-ethylmalemide–sensitive fusion protein 1, demonstrating that active release and uptake of Htt aggregates are important elements of spreading and disease progression.

scholarly journals Inhibitors of protein aggregates as novel drugs in neurodegenerative diseases

2017 ◽  
Vol 2 (3) ◽  
Author(s):  
Pietrobono D ◽  
Giacomelli C ◽  
Trincavelli ML ◽  
Daniele S ◽  
Martini C
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Aggregates ◽  
Novel Drugs

scholarly journals Lipid Metabolism Influence on Neurodegenerative Disease Progression: Is the Vehicle as Important as the Cargo?

2021 ◽  
Vol 14 ◽  
Author(s):  
Raja Elizabeth Estes ◽  
Bernice Lin ◽  
Arnav Khera ◽  
Marie Ynez Davis
Keyword(s):  
Lipid Metabolism ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Disease Progression ◽  
Protein Aggregates ◽  
Disease Etiology ◽  
Abnormal Protein ◽  
System A ◽  
Novel Therapeutic

Many neurodegenerative diseases are characterized by abnormal protein aggregates, including the two most common neurodegenerative diseases Alzheimer’s disease (AD) and Parkinson’s disease (PD). In the global search to prevent and treat diseases, most research has been focused on the early stages of the diseases, including how these pathogenic protein aggregates are initially formed. We argue, however, that an equally important aspect of disease etiology is the characteristic spread of protein aggregates throughout the nervous system, a key process in disease progression. Growing evidence suggests that both alterations in lipid metabolism and dysregulation of extracellular vesicles (EVs) accelerate the spread of protein aggregation and progression of neurodegeneration, both in neurons and potentially in surrounding glia. We will review how these two pathways are intertwined and accelerate the progression of AD and PD. Understanding how lipid metabolism, EV biogenesis, and EV uptake regulate the spread of pathogenic protein aggregation could reveal novel therapeutic targets to slow or halt neurodegenerative disease progression.

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