scholarly journals Prion-like Mechanism in Amyotrophic Lateral Sclerosis: are Protein Aggregates the Key?

2015 ◽  
Vol 24 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Shynrye Lee ◽  
Hyung-Jun Kim
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Aggregates ◽  
Lateral Sclerosis

USP10 inhibits aberrant cytoplasmic aggregation of TDP-43 by promoting stress granule clearance

2022 ◽  
Author(s):  
Masahiko Takahashi ◽  
Hiroki Kitaura ◽  
Akiyoshi Kakita ◽  
Taichi Kakihana ◽  
Yoshinori Katsuragi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Proteasome Inhibitor ◽  
Rna Binding ◽  
Protein Aggregates ◽  
Causative Factor ◽  
Stress Conditions ◽  
Dependent Manner ◽  
Cytoplasmic Protein ◽  
Als Patients ◽  
Lateral Sclerosis

TDP-43 is a causative factor of amyotrophic lateral sclerosis (ALS). Cytoplasmic TDP-43 aggregates in neurons are a hallmark pathology of ALS. Under various stress conditions, TDP-43 localizes sequentially to two cytoplasmic protein aggregates: stress granules (SGs) first, and then aggresomes. Accumulating evidence suggests that delayed clearance of TDP-43-positive SGs is associated with pathological TDP-43 aggregates in ALS. We found that USP10 promotes the clearance of TDP-43-positive SGs in cells treated with proteasome inhibitor, thereby promoting the formation of TDP-43-positive aggresomes, and the depletion of USP10 increases the amount of insoluble TDP-35, a cleaved product of TDP-43, in the cytoplasm. TDP-35 interacted with USP10 in an RNA-binding dependent manner; however, impaired RNA-binding of TDP-35 reduced the localization in SGs and aggresomes and induced USP10-negative TDP-35 aggregates. Immunohistochemistry showed that most of the cytoplasmic TDP-43/TDP-35-aggregates in the neurons of ALS patients were USP10-negative. Our findings suggest that USP10 inhibits aberrant aggregation of TDP-43/TDP-35 in the cytoplasm of neuronal cells by promoting the clearance of TDP-43/TDP-35-positive SGs and facilitating the formation of TDP-43/TDP-35-positive aggresomes.

scholarly journals Amyotrophic Lateral Sclerosis and Autophagy: Dysfunction and Therapeutic Targeting

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2413
Author(s):  
Azin Amin ◽  
Nirma D. Perera ◽  
Philip M. Beart ◽  
Bradley J. Turner ◽  
Fazel Shabanpoor
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Protein Aggregates ◽  
Misfolded Proteins ◽  
Protein Aggregate ◽  
In Vivo Models ◽  
Primary Stress ◽  
Lateral Sclerosis

Over the past 20 years, there has been a drastically increased understanding of the genetic basis of Amyotrophic Lateral Sclerosis. Despite the identification of more than 40 different ALS-causing mutations, the accumulation of neurotoxic misfolded proteins, inclusions, and aggregates within motor neurons is the main pathological hallmark in all cases of ALS. These protein aggregates are proposed to disrupt cellular processes and ultimately result in neurodegeneration. One of the main reasons implicated in the accumulation of protein aggregates may be defective autophagy, a highly conserved intracellular “clearance” system delivering misfolded proteins, aggregates, and damaged organelles to lysosomes for degradation. Autophagy is one of the primary stress response mechanisms activated in highly sensitive and specialised neurons following insult to ensure their survival. The upregulation of autophagy through pharmacological autophagy-inducing agents has largely been shown to reduce intracellular protein aggregate levels and disease phenotypes in different in vitro and in vivo models of neurodegenerative diseases. In this review, we explore the intriguing interface between ALS and autophagy, provide a most comprehensive summary of autophagy-targeted drugs that have been examined or are being developed as potential treatments for ALS to date, and discuss potential therapeutic strategies for targeting autophagy in ALS.

scholarly journals Aberrant Stress Granule Dynamics and Aggrephagy in ALS Pathogenesis

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2247
Author(s):  
Yi Zhang ◽  
Jiayu Gu ◽  
Qiming Sun
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Phase Separation ◽  
Gene Mutations ◽  
Stress Granules ◽  
Protein Aggregates ◽  
Toxic Protein ◽  
Selective Autophagy ◽  
Dynamic Assembly ◽  
Autophagy Pathway ◽  
Lateral Sclerosis

Stress granules are conserved cytosolic ribonucleoprotein (RNP) compartments that undergo dynamic assembly and disassembly by phase separation in response to stressful conditions. Gene mutations may lead to aberrant phase separation of stress granules eliciting irreversible protein aggregations. A selective autophagy pathway called aggrephagy may partially alleviate the cytotoxicity mediated by these protein aggregates. Cells must perceive when and where the stress granules are transformed into toxic protein aggregates to initiate autophagosomal engulfment for subsequent autolysosomal degradation, therefore, maintaining cellular homeostasis. Indeed, defective aggrephagy has been causally linked to various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In this review, we discuss stress granules at the intersection of autophagy and ALS pathogenesis.

scholarly journals Defective Oligodendroglial Lineage and Demyelination in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 22 (7) ◽  
pp. 3426
Author(s):  
Elisabeth Traiffort ◽  
Séverine Morisset-Lopez ◽  
Mireille Moussaed ◽  
Amina Zahaf
Keyword(s):  
Skeletal Muscle ◽  
Amyotrophic Lateral Sclerosis ◽  
Animal Models ◽  
Glial Cells ◽  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Axonal Injury ◽  
Protein Aggregates ◽  
Present Review ◽  
Lateral Sclerosis

Motor neurons and their axons reaching the skeletal muscle have long been considered as the best characterized targets of the degenerative process observed in amyotrophic lateral sclerosis (ALS). However, the involvement of glial cells was also more recently reported. Although oligodendrocytes have been underestimated for a longer time than other cells, they are presently considered as critically involved in axonal injury and also conversely constitute a target for the toxic effects of the degenerative neurons. In the present review, we highlight the recent advances regarding oligodendroglial cell involvement in the pathogenesis of ALS. First, we present the oligodendroglial cells, the process of myelination, and the tight relationship between axons and myelin. The histological abnormalities observed in ALS and animal models of the disease are described, including myelin defects and oligodendroglial accumulation of pathological protein aggregates. Then, we present data that establish the existence of dysfunctional and degenerating oligodendroglial cells, the chain of events resulting in oligodendrocyte degeneration, and the most recent molecular mechanisms supporting oligodendrocyte death and dysfunction. Finally, we review the arguments in support of the primary versus secondary involvement of oligodendrocytes in the disease and discuss the therapeutic perspectives related to oligodendrocyte implication in ALS pathogenesis.

scholarly journals Analysis of Circulating Protein Aggregates Reveals Pathological Hallmarks of Amyotrophic Lateral Sclerosis

2020 ◽  
Author(s):  
Rocco Adiutori ◽  
Fabiola Puentes ◽  
Michael Bremang ◽  
Vittoria Lombardi ◽  
Irene Zubiri ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Cell Lines ◽  
High Performance ◽  
Biological Effects ◽  
Protein Aggregates ◽  
Neuromuscular Disorder ◽  
System Level ◽  
Plasma Samples ◽  
Aggregation Propensity ◽  
Lateral Sclerosis

Abstract Background: plasma proteins composition reflects the inflammatory and metabolic state of an organism and can be predictive of system-level and organ-specific pathologies. Circulating protein aggregates (CPA) are enriched with heavy chain neurofilaments (NfH), axonal proteins involved in brain protein aggregates (BPA) formation and recently identified as biomarkers of the fatal neuromuscular disorder amyotrophic lateral sclerosis (ALS). Methods: here we use mass spectrometry and brain-enhanced TMTcalibrator™-based proteomics to evaluate the composition and the brain-derived protein component of CPA extracted from ALS and healthy controls (HC) plasma samples using high-performance ultracentrifugation. We also test CPA and BPA proteins aggregation propensity and the resistance to proteases digestion by trypsin, chymotrypsin, calpain and enterokinase of NFH within aggregates. Finally, we study CPA biological effects on neuronal and endothelial cell lines. Results: electron microscopy confirms the presence in CPA of electron-dense macromolecular particles appearing as either large globular or as small filamentous formations. CPA from ALS are enriched with proteasome system proteins while HC CPA show a prominent expression of proteins involved in metabolism. CPA enterokinase digestion in ALS generates 171 and 31 KDa NfH fragments not seen in HC samples. Compared to the whole human proteome, proteins within CPA and BPA show distinct chemical features of aggregation propensity, which appear dependent on the tissue or fluid of origin and not on the healthy or pathological source of plasma. The use of a TMTcalibrator™ proteomics workflow reveals 4973 brain-derived low-abundance proteins in CPA, including products of translation of 24 ALS risk genes. 285 (5.7%) are regulated in ALS (p < 0.05) and belong to biochemical pathways previously linked to ALS pathogenesis and aggregates formation. CPA from both ALS and HC have a higher effect on hCMEC/D3 endothelial and PC12 neuronal cells viability than immunoglobulins extracted from the same plasma samples. Compared to HC, CPA from ALS plasma samples exert a higher toxic effect on both cell lines at lower concentrations.Conclusions: this study demonstrates that CPA are significantly enriched with brain proteins which are representative of ALS pathology and a potential source of biomarkers and therapeutic targets for this incurable disorder.

scholarly journals NFκB is a central regulator of protein quality control in response to protein aggregation stresses via autophagy modulation

2016 ◽  
Vol 27 (11) ◽  
pp. 1712-1727 ◽  
Author(s):  
Mathieu Nivon ◽  
Loïc Fort ◽  
Pascale Muller ◽  
Emma Richet ◽  
Stéphanie Simon ◽  
...  
Keyword(s):  
Quality Control ◽  
Amyotrophic Lateral Sclerosis ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Protein Aggregates ◽  
Familial Amyotrophic Lateral Sclerosis ◽  
Myofibrillar Myopathy ◽  
Conformational Diseases ◽  
Lateral Sclerosis ◽  
Stimulation Of

During cell life, proteins often misfold, depending on particular mutations or environmental changes, which may lead to protein aggregates that are toxic for the cell. Such protein aggregates are the root cause of numerous diseases called “protein conformational diseases,” such as myofibrillar myopathy and familial amyotrophic lateral sclerosis. To fight against aggregates, cells are equipped with protein quality control mechanisms. Here we report that NFκB transcription factor is activated by misincorporation of amino acid analogues into proteins, inhibition of proteasomal activity, expression of the R120G mutated form of HspB5 (associated with myofibrillar myopathy), or expression of the G985R and G93A mutated forms of superoxide dismutase 1 (linked to familial amyotrophic lateral sclerosis). This noncanonical stimulation of NFκB triggers the up-regulation of BAG3 and HspB8 expression, two activators of selective autophagy, which relocalize to protein aggregates. Then NFκB-dependent autophagy allows the clearance of protein aggregates. Thus NFκB appears as a central and major regulator of protein aggregate clearance by modulating autophagic activity. In this context, the pharmacological stimulation of this quality control pathway might represent a valuable strategy for therapies against protein conformational diseases.

Wild-type Cu/Zn superoxide dismutase (SOD1) does not facilitate, but impedes the formation of protein aggregates of amyotrophic lateral sclerosis causing mutant SOD1

2009 ◽  
Vol 36 (2) ◽  
pp. 331-342 ◽  
Author(s):  
Heidrun Witan ◽  
Philipp Gorlovoy ◽  
Ali M. Kaya ◽  
Ingrid Koziollek-Drechsler ◽  
Harald Neumann ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Protein Aggregates ◽  
Wild Type ◽  
Mutant Sod1 ◽  
Lateral Sclerosis

scholarly journals Analysis of circulating protein aggregates reveals pathological hallmarks of amyotrophic lateral sclerosis

2020 ◽  
Author(s):  
Rocco Adiutori ◽  
Fabiola Puentes ◽  
Michael Bremang ◽  
Vittoria Lombardi ◽  
Irene Zubiri ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Aggregation ◽  
Neurodegenerative Disorder ◽  
Neuronal Cell ◽  
Protein Composition ◽  
Protein Aggregates ◽  
System Level ◽  
Alternative Source ◽  
Peripheral Protein ◽  
Lateral Sclerosis

AbstractBlood-based biomarkers can be informative of brain disorders where protein aggregation play a major role. The proteome of plasma and circulating protein aggregates (CPA) reflect the inflammatory and metabolic state of the organism and can be predictive of system-level and/or organ-specific pathologies. CPA are enriched with heavy chain neurofilaments (NfH), key axonal constituents involved in brain aggregates formation and biomarkers of the fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Here we show that CPA and brain protein aggregates (BPA) from ALS differ in protein composition and appear as a combination of electron-dense large globular and small filamentous formations on transmission electron microscopy. CPA are highly enriched with proteins involved in the proteasome and energy metabolism. Compared to the human proteome, proteins within aggregates show distinct and tissue-dependent chemical features of aggregation propensity. The use of a TMTcalibrator™ proteomics workflow with ALS brain as calibrant reveals 4973 brain-derived low-abundance proteins in CPA, including the products of translation of 24 ALS risk genes. 285 of these (5.7%) are regulated in ALS CPA including FUS (p<0.05). CPA from both ALS and healthy controls affect cell viability when testing endothelial and PC12 neuronal cell lines, while CPA from ALS exert a more toxic effect at lower concentrations. The analysis of resistance to protease enzymes hydrolysis indicates an ALS-specific digestion pattern for NfH using enterokinase. This study reveals how peripheral protein aggregates are significantly enriched with brain proteins which are highly representative of ALS pathology and a potential alternative source of biomarkers and therapeutic targets for this incurable disorder.Significance StatementMolecular mechanism of neurodegeneration like protein aggregation are important brain-specific alterations which need to be addressed therapeutically. Recently described fluid biomarkers of neurodegenerative disorders provide means for stratification and monitoring of disease progression. Here we show that circulating protein aggregates are easily accessible in blood and reproduce important features of brain pathology for an incurable disorder like amyotrophic lateral sclerosis. They represent a source of biomarkers and of novel therapeutics for ALS.

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