scholarly journals Supersaturation is a major driving force for protein aggregation in neurodegenerative diseases

2015 ◽  
Vol 36 (2) ◽  
pp. 72-77 ◽  
Author(s):  
Prajwal Ciryam ◽  
Rishika Kundra ◽  
Richard I. Morimoto ◽  
Christopher M. Dobson ◽  
Michele Vendruscolo
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Driving Force

scholarly journals Observation of liquid-liquid phase separation of ataxin-3 and quantitative evaluation of its concentration in a single droplet using Raman microscopy

2021 ◽  
Author(s):  
Kazuki Murakami ◽  
Shinji Kajimoto ◽  
Daiki Shibata ◽  
Kunisato Kuroi ◽  
Fumihiko Fujii ◽  
...  
Keyword(s):  
Phase Separation ◽  
Liquid Phase ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Quantitative Evaluation ◽  
Raman Microscopy ◽  
Liquid Phase Separation ◽  
Biological Processes ◽  
Single Droplet ◽  
Liquid Liquid Phase Separation

Liquid–liquid phase separation (LLPS) plays an important role in a variety of biological processes and is also associated with protein aggregation in neurodegenerative diseases. Quantification of LLPS is necessary to...

The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Proteostasis Factors

2021 ◽  
Author(s):  
Benjamin C Creekmore ◽  
Yi-Wei Chang ◽  
Edward B Lee
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Electron Tomography ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
X Ray Crystallography ◽  
New Information ◽  
A Cell ◽  
Regulate Protein

Abstract Neurodegenerative diseases are characterized by the accumulation of misfolded proteins. This protein aggregation suggests that abnormal proteostasis contributes to aging-related neurodegeneration. A better fundamental understanding of proteins that regulate proteostasis may provide insight into the pathophysiology of neurodegenerative disease and may perhaps reveal novel therapeutic opportunities. The 26S proteasome is the key effector of the ubiquitin-proteasome system responsible for degrading polyubiquitinated proteins. However, additional factors, such as valosin-containing protein (VCP/p97/Cdc48) and C9orf72, play a role in regulation and trafficking of substrates through the normal proteostasis systems of a cell. Nonhuman AAA+ ATPases, such as the disaggregase Hsp104, also provide insights into the biochemical processes that regulate protein aggregation. X-ray crystallography and cryo-electron microscopy (cryo-EM) structures not bound to substrate have provided meaningful information about the 26S proteasome, VCP, and Hsp104. However, recent cryo-EM structures bound to substrate have provided new information about the function and mechanism of these proteostasis factors. Cryo-EM and cryo-electron tomography data combined with biochemical data have also increased the understanding of C9orf72 and its role in maintaining proteostasis. These structural insights provide a foundation for understanding proteostasis mechanisms with near-atomic resolution upon which insights can be gleaned regarding the pathophysiology of neurodegenerative diseases.

Biochemical and immunological aspects of protein aggregation in neurodegenerative diseases

2014 ◽  
Vol 11 (6) ◽  
pp. 1503-1512 ◽  
Author(s):  
Fatemeh Shojaei ◽  
Naemeh Tavakolinia ◽  
Adeleh Divsalar ◽  
Thomas Haertlé ◽  
Ali Akbar Saboury ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Aggregation

scholarly journals Phase separation of proSAAS into spheres results in core sequestration of TDP-43216-414 aggregates

2020 ◽  
Author(s):  
Juan R. Peinado ◽  
Kriti Chaplot ◽  
Timothy S. Jarvela ◽  
Edward Barbieri ◽  
James Shorter ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Phase Separation ◽  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Model System ◽  
Chaperone Activity ◽  
Chaperone Proteins ◽  
Cytotoxic Effects ◽  
Vital Functions

SUMMARYChaperone proteins perform vital functions in the maintenance of cellular proteostasis and play important roles during the development of neurodegenerative diseases involving protein aggregation. We have previously reported that a secreted neuronal chaperone known as proSAAS exhibits potent chaperone activity in vitro against protein aggregation and blocks the cytotoxic effects of amyloid and α-synuclein oligomers. Here we report that overexpression of proSAAS generates dense, membraneless 2 μm spheres which can increase by fusion up to 4 μM during expression within the cytoplasm. The presence of dense proSAAS spheres was confirmed using electron microscopy. ProSAAS spheres selectively sequestered GFP-TDP-43216-414 within their cores, resulting in cellular redistribution and retardation of degradation. ProSAAS expression was protective against TDP-43 cytotoxicity in a yeast model system. Aggregate sequestration via proSAAS encapsulation may provide protection from cell-to-cell transmission of aggregates and explain the as-yet unclear mechanism underlying the cytoprotective chaperone action of proSAAS.

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.

scholarly journals Compromised function of the ESCRT pathway promotes endolysosomal escape of tau seeds and propagation of tau aggregation

2019 ◽  
Author(s):  
John J. Chen ◽  
Diane L. Nathaniel ◽  
Preethi Raghavan ◽  
Maxine Nelson ◽  
Ruilin Tian ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Frontotemporal Dementia ◽  
Human Cell ◽  
Membrane Repair ◽  
Critical Step ◽  
Crispr Interference ◽  
Escrt Machinery ◽  
Systematic Understanding ◽  
Tau Aggregation

ABSTRACTIntercellular propagation of protein aggregation is emerging as a key mechanism in the progression of several neurodegenerative diseases, including Alzheimer’s Disease and frontotemporal dementia. However, we lack a systematic understanding of the cellular path-ways controlling prion-like propagation. To uncover such pathways, we performed CRISPR interference (CRISPRi) screens in a human cell-based model of propagation of tau aggregation. Our screens uncovered that knockdown of several components of the ESCRT machinery, including CHMP6, or CHMP2A in combination with CHMP2B (a gene linked to familial fronto-temporal dementia), promote propagation of tau aggregation. We found that knockdown of these genes caused damage to endolysosomal membranes, consistent with a role for the ESCRT pathway in endolysosomal membrane repair. Leakiness of the endolysosomal compartment significantly enhanced prion-like propagation of tau aggregation, likely by making tau seeds more available to pools of cytoplasmic tau. Together, these findings suggest that endolysosomal escape is a critical step in tau propagation.

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