scholarly journals ALS-Related Mutant SOD1 Aggregates Interfere with Mitophagy by Sequestering the Autophagy Receptor Optineurin

2020 ◽  
Vol 21 (20) ◽  
pp. 7525
Author(s):  
Yeong Jin Tak ◽  
Ju-Hwang Park ◽  
Hyangshuk Rhim ◽  
Seongman Kang
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Cellular Cytotoxicity ◽  
Superoxide Dismutase 1 ◽  
Gene Encoding ◽  
Abnormal Protein ◽  
Mutant Sod1 ◽  
Familial Als ◽  
The Relationship ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive demise of motor neurons. One of the causes of familial ALS is the mutation of the gene encoding superoxide dismutase 1 (SOD1), which leads to abnormal protein aggregates. How SOD1 aggregation drives ALS is still poorly understood. Recently, ALS pathogenesis has been functionally implicated in mitophagy, specifically the clearance of damaged mitochondria. Here, to understand this mechanism, we investigated the relationship between the mitophagy receptor optineurin and SOD1 aggregates. We found that mutant SOD1 (mSOD1) proteins associate with and then sequester optineurin, which is required to form the mitophagosomes, to aggregates in N2a cells. Optineurin recruitment into mSOD1 aggregates resulted in a reduced mitophagy flux. Furthermore, we observed that an exogenous augmentation of optineurin alleviated the cellular cytotoxicity induced by mSOD1. Taken together, these studies demonstrate that ALS-linked mutations in SOD1 interfere with the mitophagy process through optineurin sequestration, suggesting that the accumulation of damaged mitochondria may play a crucial role in the pathophysiological mechanisms contributing to ALS.

scholarly journals Absence of neurofilaments reduces the selective vulnerability of motor neurons and slows disease caused by a familial amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutant

1998 ◽  
Vol 95 (16) ◽  
pp. 9631-9636 ◽  
Author(s):  
Toni L. Williamson ◽  
Lucie I. Bruijn ◽  
Qinzhang Zhu ◽  
Karen L. Anderson ◽  
Scott D. Anderson ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Superoxide Dismutase ◽  
Motor Neurons ◽  
Selective Vulnerability ◽  
Superoxide Dismutase 1 ◽  
Filament Assembly ◽  
Progression Of Disease ◽  
Familial Als ◽  
Sod1 Mutant ◽  
Lateral Sclerosis

Mutations in superoxide dismutase 1 (SOD1), the only proven cause of amyotrophic lateral sclerosis (ALS), provoke disease through an unidentified toxic property. Neurofilament aggregates are pathologic hallmarks of both sporadic and SOD1-mediated familial ALS. By deleting NF-L, the major neurofilament subunit required for filament assembly, onset and progression of disease caused by familial ALS-linked SOD1 mutant G85R are significantly slowed, while selectivity of mutant-mediated toxicity for motor neurons is reduced. In NF-L-deleted animals, levels of the two remaining neurofilament subunits, NF-M and NF-H, are markedly reduced in axons but are elevated in motor neuron cell bodies. Thus, while neither perikaryal nor axonal neurofilaments are essential for SOD1-mediated disease, the absence of assembled neurofilaments both diminishes selective vulnerability and slows SOD1G85R mutant-mediated toxicity to motor neurons.

scholarly journals A neurotoxic peripherin splice variant in a mouse model of ALS

2003 ◽  
Vol 160 (6) ◽  
pp. 939-949 ◽  
Author(s):  
Janice Robertson ◽  
Mohammad M. Doroudchi ◽  
Minh Dang Nguyen ◽  
Heather D. Durham ◽  
Michael J. Strong ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Motor Neurons ◽  
Splice Variants ◽  
Superoxide Dismutase 1 ◽  
Specific Antibodies ◽  
Axonal Spheroids ◽  
Familial Als ◽  
Nif Proteins ◽  
Lateral Sclerosis

Peripherin, a neuronal intermediate filament (nIF) protein found associated with pathological aggregates in motor neurons of patients with amyotrophic lateral sclerosis (ALS) and of transgenic mice overexpressing mutant superoxide dismutase-1 (SOD1G37R), induces the selective degeneration of motor neurons when overexpressed in transgenic mice. Mouse peripherin is unique compared with other nIF proteins in that three peripherin isoforms are generated by alternative splicing. Here, the properties of the peripherin splice variants Per 58, Per 56, and Per 61 have been investigated in transfected cell lines, in primary motor neurons, and in transgenic mice overexpressing peripherin or overexpressing SOD1G37R. Of the three isoforms, Per 61 proved to be distinctly neurotoxic, being assembly incompetent and inducing degeneration of motor neurons in culture. Using isoform-specific antibodies, Per 61 expression was detected in motor neurons of SOD1G37R transgenic mice but not of control or peripherin transgenic mice. The Per 61 antibody also selectively labeled motor neurons and axonal spheroids in two cases of familial ALS and immunoprecipitated a higher molecular mass peripherin species from disease tissue. This evidence suggests that expression of neurotoxic splice variants of peripherin may contribute to the neurodegenerative mechanism in ALS.

scholarly journals The Emerging Role of DNA Damage in the Pathogenesis of the C9orf72 Repeat Expansion in Amyotrophic Lateral Sclerosis

2018 ◽  
Vol 19 (10) ◽  
pp. 3137 ◽  
Author(s):  
Anna Konopka ◽  
Julie Atkin
Keyword(s):  
Dna Damage ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Repeat Expansion ◽  
Chromosome 9 ◽  
Gene Encoding ◽  
C9orf72 Repeat Expansion ◽  
Reading Frame ◽  
Early Onset Dementia ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressing neurodegenerative disease affecting motor neurons, and frontotemporal dementia (FTD) is a behavioural disorder resulting in early-onset dementia. Hexanucleotide (G4C2) repeat expansions in the gene encoding chromosome 9 open reading frame 72 (C9orf72) are the major cause of familial forms of both ALS (~40%) and FTD (~20%) worldwide. The C9orf72 repeat expansion is known to form abnormal nuclei acid structures, such as hairpins, G-quadruplexes, and R-loops, which are increasingly associated with human diseases involving microsatellite repeats. These configurations form during normal cellular processes, but if they persist they also damage DNA, and hence are a serious threat to genome integrity. It is unclear how the repeat expansion in C9orf72 causes ALS, but recent evidence implicates DNA damage in neurodegeneration. This may arise from abnormal nucleic acid structures, the greatly expanded C9orf72 RNA, or by repeat-associated non-ATG (RAN) translation, which generates toxic dipeptide repeat proteins. In this review, we detail recent advances implicating DNA damage in C9orf72-ALS. Furthermore, we also discuss increasing evidence that targeting these aberrant C9orf72 confirmations may have therapeutic value for ALS, thus revealing new avenues for drug discovery for this disorder.

scholarly journals Lack of TNF-alpha receptor type 2 protects motor neurons in a cellular model of amyotrophic lateral sclerosis and in mutant SOD1 mice but does not affect disease progression

2015 ◽  
Vol 135 (1) ◽  
pp. 109-124 ◽  
Author(s):  
Massimo Tortarolo ◽  
Antonio Vallarola ◽  
Dario Lidonnici ◽  
Elisa Battaglia ◽  
Francesco Gensano ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
Motor Neurons ◽  
Receptor Type ◽  
Tnf Alpha ◽  
Cellular Model ◽  
Mutant Sod1 ◽  
Lateral Sclerosis

scholarly journals Early upregulation of cytosolic phospholipase A2α in motor neurons is induced by misfolded SOD1 in a mouse model of amyotrophic lateral sclerosis

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Yafa Fetfet Malada Edelstein ◽  
Yulia Solomonov ◽  
Nurit Hadad ◽  
Leenor Alfahel ◽  
Adrian Israelson ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Transgenic Mice ◽  
Motor Neurons ◽  
Dependent Manner ◽  
Mutant Sod1 ◽  
Over Expression ◽  
Cytosolic Phospholipase ◽  
Misfolded Sod1 ◽  
Lateral Sclerosis

Abstract Background Amyotrophic lateral sclerosis (ALS) is a fatal multifactorial neurodegenerative disease characterized by the selective death of motor neurons. Cytosolic phospholipase A2 alpha (cPLA2α) upregulation and activation in the spinal cord of ALS patients has been reported. We have previously shown that cPLA2α upregulation in the spinal cord of mutant SOD1 transgenic mice (SOD1G93A) was detected long before the development of the disease, and inhibition of cPLA2α upregulation delayed the disease’s onset. The aim of the present study was to determine the mechanism for cPLA2α upregulation. Methods Immunofluorescence analysis and western blot analysis of misfolded SOD1, cPLA2α and inflammatory markers were performed in the spinal cord sections of SOD1G93A transgenic mice and in primary motor neurons. Over expression of mutant SOD1 was performed by induction or transfection in primary motor neurons and in differentiated NSC34 motor neuron like cells. Results Misfolded SOD1 was detected in the spinal cord of 3 weeks old mutant SOD1G93A mice before cPLA2α upregulation. Elevated expression of both misfolded SOD1 and cPLA2α was specifically detected in the motor neurons at 6 weeks with a high correlation between them. Elevated TNFα levels were detected in the spinal cord lysates of 6 weeks old mutant SOD1G93A mice. Elevated TNFα was specifically detected in the motor neurons and its expression was highly correlated with cPLA2α expression at 6 weeks. Induction of mutant SOD1 in primary motor neurons induced cPLA2α and TNFα upregulation. Over expression of mutant SOD1 in NSC34 cells caused cPLA2α upregulation which was prevented by antibodies against TNFα. The addition of TNFα to NSC34 cells caused cPLA2α upregulation in a dose dependent manner. Conclusions Motor neurons expressing elevated cPLA2α and TNFα are in an inflammatory state as early as at 6 weeks old mutant SOD1G93A mice long before the development of the disease. Accumulated misfolded SOD1 in the motor neurons induced cPLA2α upregulation via induction of TNFα.

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.

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