scholarly journals Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains

Cell Reports ◽  
2020 ◽  
Vol 32 (7) ◽  
pp. 108050 ◽  
Author(s):  
Christian Haenig ◽  
Nir Atias ◽  
Alexander K. Taylor ◽  
Arnon Mazza ◽  
Martin H. Schaefer ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Interactome Mapping

scholarly journals Mitophagy Modulation, a New Player in the Race against ALS

2021 ◽  
Vol 22 (2) ◽  
pp. 740
Author(s):  
Enrique Madruga ◽  
Inés Maestro ◽  
Ana Martínez
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Effective Treatment ◽  
Unknown Etiology ◽  
Drug Candidates ◽  
Relevant Evidence ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that usually results in respiratory paralysis in an interval of 2 to 4 years. ALS shows a multifactorial pathogenesis with an unknown etiology, and currently lacks an effective treatment. The vast majority of patients exhibit protein aggregation and a dysfunctional mitochondrial accumulation in their motoneurons. As a result, autophagy and mitophagy modulators may be interesting drug candidates that mitigate key pathological hallmarks of the disease. This work reviews the most relevant evidence that correlate mitophagy defects and ALS, and discusses the possibility of considering mitophagy as an interesting target in the search for an effective treatment for ALS.

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.

scholarly journals Fluctuations in Protein Aggregation: Design of Preclinical Screening for Early Diagnosis of Neurodegenerative Disease

2016 ◽  
Vol 6 (3) ◽  
Author(s):  
Giulio Costantini ◽  
Zoe Budrikis ◽  
Alessandro Taloni ◽  
Alexander K. Buell ◽  
Stefano Zapperi ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Preclinical Screening

scholarly journals Therapeutic genetic variation revealed in diverse Hsp104 homologs

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Zachary M March ◽  
Katelyn Sweeney ◽  
Hanna Kim ◽  
Xiaohui Yan ◽  
Laura M Castellano ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Human Cells ◽  
C Elegans ◽  
Dopaminergic Neurodegeneration ◽  
Aaa Protein ◽  
Selective Activity

The AAA+ protein disaggregase, Hsp104, increases fitness under stress by reversing stress-induced protein aggregation. Natural Hsp104 variants might exist with enhanced, selective activity against neurodegenerative disease substrates. However, natural Hsp104 variation remains largely unexplored. Here, we screened a cross-kingdom collection of Hsp104 homologs in yeast proteotoxicity models. Prokaryotic ClpG reduced TDP-43, FUS, and α-synuclein toxicity, whereas prokaryotic ClpB and hyperactive variants were ineffective. We uncovered therapeutic genetic variation among eukaryotic Hsp104 homologs that specifically antagonized TDP-43 condensation and toxicity in yeast and TDP-43 aggregation in human cells. We also uncovered distinct eukaryotic Hsp104 homologs that selectively antagonized α-synuclein condensation and toxicity in yeast and dopaminergic neurodegeneration in C. elegans. Surprisingly, this therapeutic variation did not manifest as enhanced disaggregase activity, but rather as increased passive inhibition of aggregation of specific substrates. By exploring natural tuning of this passive Hsp104 activity, we elucidated enhanced, substrate-specific agents that counter proteotoxicity underlying neurodegeneration.

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 The role of advanced glycation end products in various types of neurodegenerative disease: a therapeutic approach

2014 ◽  
Vol 19 (3) ◽  
Author(s):  
Parveen Salahuddin ◽  
Gulam Rabbani ◽  
Rizwan Khan
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Advanced Glycation End Products ◽  
Advanced Glycation ◽  
Amadori Products ◽  
Glycation End Products ◽  
Sheet Structure ◽  
End Products ◽  
Β Sheet

AbstractProtein glycation is initiated by a nucleophilic addition reaction between the free amino group from a protein, lipid or nucleic acid and the carbonyl group of a reducing sugar. This reaction forms a reversible Schiff base, which rearranges over a period of days to produce ketoamine or Amadori products. The Amadori products undergo dehydration and rearrangements and develop a cross-link between adjacent proteins, giving rise to protein aggregation or advanced glycation end products (AGEs). A number of studies have shown that glycation induces the formation of the β-sheet structure in β-amyloid protein, α-synuclein, transthyretin (TTR), copper-zinc superoxide dismutase 1 (Cu, Zn-SOD-1), and prion protein. Aggregation of the β-sheet structure in each case creates fibrillar structures, respectively causing Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, familial amyloid polyneuropathy, and prion disease. It has been suggested that oligomeric species of glycated α-synuclein and prion are more toxic than fibrils. This review focuses on the pathway of AGE formation, the synthesis of different types of AGE, and the molecular mechanisms by which glycation causes various types of neurodegenerative disease. It discusses several new therapeutic approaches that have been applied to treat these devastating disorders, including the use of various synthetic and naturally occurring inhibitors. Modulation of the AGE-RAGE axis is now considered promising in the prevention of neurodegenerative diseases. Additionally, the review covers several defense enzymes and proteins in the human body that are important anti-glycating systems acting to prevent the development of neurodegenerative diseases.

Protein aggregation and neurodegenerative disease

2004 ◽  
Vol 10 (S7) ◽  
pp. S10-S17 ◽  
Author(s):  
Christopher A Ross ◽  
Michelle A Poirier
Keyword(s):  
Protein Aggregation ◽  
Neurodegenerative Disease

Analysis of Protein Aggregation in Neurodegenerative Disease

2013 ◽  
Vol 85 (9) ◽  
pp. 4215-4227 ◽  
Author(s):  
Jeppe T. Pedersen ◽  
Niels H. H. Heegaard
Keyword(s):  
Protein Aggregation ◽  
Neurodegenerative Disease
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