scholarly journals Corrigendum: Prion-Like Propagation of Protein Misfolding and Aggregation in Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 12 ◽  
Author(s):  
Luke McAlary ◽  
Steven S. Plotkin ◽  
Justin J. Yerbury ◽  
Neil R. Cashman
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Misfolding ◽  
Protein Misfolding And Aggregation ◽  
Lateral Sclerosis

scholarly journals Engineering therapeutic protein disaggregases

2016 ◽  
Vol 27 (10) ◽  
pp. 1556-1560 ◽  
Author(s):  
James Shorter
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Disorders ◽  
Protein Misfolding ◽  
Therapeutic Agents ◽  
Loss Of Function ◽  
Native Structure ◽  
Aaa Atpase ◽  
Protein Misfolding And Aggregation ◽  
Small Molecule Enhancers ◽  
Lateral Sclerosis

Therapeutic agents are urgently required to cure several common and fatal neurodegenerative disorders caused by protein misfolding and aggregation, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer’s disease (AD). Protein disaggregases that reverse protein misfolding and restore proteins to native structure, function, and localization could mitigate neurodegeneration by simultaneously reversing 1) any toxic gain of function of the misfolded form and 2) any loss of function due to misfolding. Potentiated variants of Hsp104, a hexameric AAA+ ATPase and protein disaggregase from yeast, have been engineered to robustly disaggregate misfolded proteins connected with ALS (e.g., TDP-43 and FUS) and PD (e.g., α-synuclein). However, Hsp104 has no metazoan homologue. Metazoa possess protein disaggregase systems distinct from Hsp104, including Hsp110, Hsp70, and Hsp40, as well as HtrA1, which might be harnessed to reverse deleterious protein misfolding. Nevertheless, vicissitudes of aging, environment, or genetics conspire to negate these disaggregase systems in neurodegenerative disease. Thus, engineering potentiated human protein disaggregases or isolating small-molecule enhancers of their activity could yield transformative therapeutics for ALS, PD, and AD.

scholarly journals All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2438
Author(s):  
Shirel Argueti-Ostrovsky ◽  
Leenor Alfahel ◽  
Joy Kahn ◽  
Adrian Israelson
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Misfolding ◽  
Proteasome Inhibition ◽  
Nucleocytoplasmic Transport ◽  
Selective Vulnerability ◽  
Inflammatory Processes ◽  
The Common ◽  
End Stage ◽  
Protein Misfolding And Aggregation ◽  
Lateral Sclerosis

Multiple neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) are being suggested to have common cellular and molecular pathological mechanisms, characterized mainly by protein misfolding and aggregation. These large inclusions, most likely, represent an end stage of a molecular cascade; however, the soluble misfolded proteins, which take part in earlier steps of this cascade, are the more toxic players. These pathological proteins, which characterize each specific disease, lead to the selective vulnerability of different neurons, likely resulting from a combination of different intracellular mechanisms, including mitochondrial dysfunction, ER stress, proteasome inhibition, excitotoxicity, oxidative damage, defects in nucleocytoplasmic transport, defective axonal transport and neuroinflammation. Damage within these neurons is enhanced by damage from the nonneuronal cells, via inflammatory processes that accelerate the progression of these diseases. In this review, while acknowledging the hallmark proteins which characterize the most common NDDs; we place specific focus on the common overlapping mechanisms leading to disease pathology despite these different molecular players and discuss how this convergence may occur, with the ultimate hope that therapies effective in one disease may successfully translate to another.

scholarly journals Bentonite Exposure in Western Pacific Amyotrophic Lateral Sclerosis/ Parkinsonism Dementia Complex and Neurodegenerative Diseases

2020 ◽  
Author(s):  
Kavitha Reddy
Keyword(s):  
Risk Factors ◽  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Western Pacific ◽  
Lateral Sclerosis

Neurodegenerative diseases of protein misfolding affect humans and animals. In humans, these diseases include Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Western Pacific amyotrophic lateral sclerosis and Parkinsonism-dementia complex (ALS/PDC). Mineral exposure may be important in the pathogenesis of protein misfolding cascades. The possible association of bentonite, montmorillonite, and mineral risk factors with Alzheimer’s disease, Parkinson’s disease, ALS, and Western Pacific ALS/PDC is analyzed and discussed.

scholarly journals A Screen to Identify Cellular Modulators of Soluble Levels of an Amyotrophic Lateral Sclerosis (ALS)–Causing Mutant SOD1

2011 ◽  
Vol 16 (9) ◽  
pp. 974-985 ◽  
Author(s):  
Balajee R. Somalinga ◽  
Gregory A. Miller ◽  
Hiba T. Malik ◽  
W. Christian Wigley ◽  
Philip J. Thomas
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
High Throughput Screening ◽  
Protein Misfolding ◽  
Mammalian Cells ◽  
Protein Solubility ◽  
Global Scale ◽  
Cdna Clones ◽  
Mutant Sod1 ◽  
Cellular Targets ◽  
Lateral Sclerosis

The molecular pathology of many protein misfolding, toxic gain-of-function diseases, such as amyotrophic lateral sclerosis (ALS), is not well understood. Although protein misfolding and aggregation are common themes in these diseases, efforts to identify cellular factors that regulate this process in an unbiased fashion and on a global scale have been lacking. Using an adapted version of an extant β-gal-based protein solubility assay, an expression screen for cellular modulators of solubility of an ALS-causing mutant SOD1 was carried out in mammalian cells. Following fluorescence-activated cell sorting enrichment of a mouse spinal cord cDNA library for gene products that increased SOD1 solubility, high-throughput screening of the cDNA pools from this enriched fraction was employed to identify pools containing relevant modulators. Positive pools, containing approximately 10 cDNA clones each, were diluted and rescreened iteratively until individual clones that improved SOD1 folding/solubility were identified. Genes with profound effects in the solubility assay were selected for validation by independent biochemical assays. Six of 10 validated genes had a significant effect on SOD1 solubility and folding in a SOD1 promoter-driven β-gal assay, indicating that global screening of cellular targets using such protein solubility/folding assay is viable and can be adapted for other misfolding diseases.

Using yeast models to probe the molecular basis of amyotrophic lateral sclerosis

2011 ◽  
Vol 39 (5) ◽  
pp. 1482-1487 ◽  
Author(s):  
Emma L. Bastow ◽  
Campbell W. Gourlay ◽  
Mick F. Tuite
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Molecular Basis ◽  
Protein Misfolding ◽  
Model Organism ◽  
Yeast Saccharomyces Cerevisiae ◽  
Mutant Sod1 ◽  
Fused In Sarcoma ◽  
Functional Inactivation ◽  
Lateral Sclerosis

ALS (amyotrophic lateral sclerosis) is a fatal neurodegenerative disease attributable to the death of motor neurons. Associated with ALS are mutations in the genes encoding SOD1 (superoxide dismutase 1), FUS (fused in Sarcoma) protein and TDP-43 (TAR DNA-binding protein-43) each of which leads to aggregation of the respective protein. For example, the ALS-associated mutations in the hSOD1 (human SOD1) gene typically destabilize the native SOD homodimer, leading to misfolding, aggregation and degradation of SOD1. The ALS-associated pathology is not a consequence of the functional inactivation of SOD1 itself, but is rather due to a toxic gain-of-function triggered by mutant SOD1. Recently, the molecular basis of a number of human neurodegenerative diseases resulting from protein misfolding and aggregation, including fALS (familial ALS), was probed by using the baker's yeast, Saccharomyces cerevisiae, as a highly tractable model. Such studies have, for example, identified novel mutant SOD1-specific interactions and demonstrated that mutant SOD1 disrupts mitochondrial homoeostasis. Features of ALS associated with TDP-43 aggregation have also been recapitulated in S. cerevisiae including the identification of modulators of the toxicity of TDP-43. In this paper, we review recent studies of ALS pathogenesis using S. cerevisiae as a model organism and summarize the potential mechanisms involved in ALS progression.

scholarly journals Western Faculty Profile: Dr. Martin L. Duennwald

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Soojie Hong
Keyword(s):  
Quality Control ◽  
Amyotrophic Lateral Sclerosis ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Assistant Professor ◽  
Cellular Protein ◽  
Independent Research ◽  
Biomedical Research Institute ◽  
Control Protein ◽  
Lateral Sclerosis

Dr. Martin L. Duennwald is a researcher and assistant professor at Western University. After conducting independent research at the Boston Biomedical Research Institute, he came to Western University in 2012 where he started the Duennwald Lab. His lab focuses on cellular protein quality control, protein misfolding and their pathological consequences in neurodegenerative diseases such as Huntington’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis (ALS).

scholarly journals Random forest modelling of neuropathological features identifies microglial activation as an accurate pathological classifier of C9orf72-related amyotrophic lateral sclerosis

2021 ◽  
Author(s):  
Olivia M Rifai ◽  
James Longden ◽  
Judi O'Shaughnessy ◽  
Michael DE Sewell ◽  
Karina McDade ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Random Forest ◽  
Protein Misfolding ◽  
Microglial Activation ◽  
Rna Binding ◽  
Disease Status ◽  
Forest Modelling ◽  
Immunohistochemical Markers ◽  
Hexanucleotide Repeat ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are regarded as two ends of a pathogenetic spectrum, termed ALS-frontotemporal spectrum disorder (ALS-FTSD). However, it is currently difficult to predict where on the spectrum an individual will lie, especially for patients with C9orf72 hexanucleotide repeat expansions (HRE), a mutation associated with both ALS and FTD. It has been shown that both inflammation and protein misfolding influence aspects of ALS and ALS-FTSD disease pathogenesis, such as the manifestation or severity of motor or cognitive symptoms. Previous studies have highlighted markers which may influence C9orf72-associated disease presentation in a targeted fashion, though there has yet to be a systematic and quantitative assessment of common immunohistochemical markers to investigate the significance of these pathways in an unbiased manner. Here we report the first extensive digital pathological assessment with random forest modelling of pathological markers often used in neuropathology practice. This study profiles glial activation and protein misfolding in a cohort of deeply clinically profiled post-mortem tissue from patients with a C9orf72 HRE, who either met the criteria for a diagnosis of ALS or ALS-FTSD. We show that microglial immunohistochemical staining features, both morphological and spatial, are the best independent classifiers of disease status and that clinicopathological associations exist between microglial activation status and cognitive dysfunction in ALS-FTSD patients with C9orf72 HRE. Furthermore, we show that spatially resolved changes in FUS staining are also an accurate predictor of disease status, implying that liquid-liquid phase shift of this aggregation-prone RNA-binding protein may be important in ALS caused by a C9orf72 HRE. Our findings provide further support to the hypothesis of dysfunctional immune regulation and proteostasis in the pathogenesis of C9orf72 ALS and provide a framework for digital analysis of commonly used neuropathological stains as a tool to enrich our understanding of clinicopathological associations between cohorts.

Sign in / Sign up

Export Citation Format

Share Document