SOD1-positive aggregate accumulation in the CNS predicts slower disease progression and increased longevity in a mutant SOD1 mouse model of ALS

Gill, Cindy; Phelan, James; Hatzipetros, Theo; Kidd, Joshua D.; Tassinari, Valerie R.; Levine, Beth A.; Wang, Monica Z.; Moreno, Andrew; Thompson, Kenneth; Maier, Marcel; Grimm, Jan; Gill, Alan; Vieira, Fernando

doi:10.1038/s41598-019-43164-z

Cited by 55 publications

(56 citation statements)

References 51 publications

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“…However, true insoluble aggregates only appear at late stages in transgenic mouse models, after or disconnected from the onset of ALS-like symptoms, indicating they may be a response to toxicity or innocuous bi-product rather than a cause. Highlighting this point, Gill et al (2019) found that the amount of aggregated SOD1 in transgenic mouse spinal cord was inversely proportional to disease progression as measured by NeuroScore. Thus, mice fair better if they sequester more SOD1 in aggregates.…”

Section: Are Aggregates Toxic?mentioning

confidence: 94%

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The biophysics of superoxide dismutase-1 and amyotrophic lateral sclerosis

Wright

Antonyuk

Hasnain

2019

Quart. Rev. Biophys.

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Few proteins have come under such intense scrutiny as superoxide dismutase-1 (SOD1). For almost a century, scientists have dissected its form, function and then later its malfunction in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We now know SOD1 is a zinc and copper metalloenzyme that clears superoxide as part of our antioxidant defence and respiratory regulation systems. The possibility of reduced structural integrity was suggested by the first crystal structures of human SOD1 even before deleterious mutations in thesod1gene were linked to the ALS. This concept evolved in the intervening years as an impressive array of biophysical studies examined the characteristics of mutant SOD1 in great detail. We now recognise how ALS-related mutations perturb the SOD1 maturation processes, reduce its ability to fold and reduce its thermal stability and half-life. Mutant SOD1 is therefore predisposed to monomerisation, non-canonical self-interactions, the formation of small misfolded oligomers and ultimately accumulation in the tell-tale insoluble inclusions found within the neurons of ALS patients. We have also seen that several post-translational modifications could push wild-type SOD1 down this toxic pathway. Recently we have come to view ALS as a prion-like disease where both the symptoms, and indeed SOD1 misfolding itself, are transmitted to neighbouring cells. This raises the possibility of intervention after the initial disease presentation. Several small-molecule and biologic-based strategies have been devised which directly target the SOD1 molecule to change the behaviour thought to be responsible for ALS. Here we provide a comprehensive review of the many biophysical advances that sculpted our view of SOD1 biology and the recent work that aims to apply this knowledge for therapeutic outcomes in ALS.

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Section: Are Aggregates Toxic?mentioning

confidence: 94%

“…Highlighting this point, Gill et al . (2019) found that the amount of aggregated SOD1 in transgenic mouse spinal cord was inversely proportional to disease progression as measured by NeuroScore. Thus, mice fair better if they sequester more SOD1 in aggregates.…”

Section: Sod1 Aggregation In Alsmentioning

confidence: 99%

The biophysics of superoxide dismutase-1 and amyotrophic lateral sclerosis

Wright

Antonyuk

Hasnain

2019

Quart. Rev. Biophys.

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“…Protein aggregates positive for TDP-43 [ 36 , 205 ], neurofilament [ 41 ], FUS [ 87 ], or SOD1 [ 206 ] are observed in the vast majority of ALS patients, with TDP-43 being present in as many as 98% of sporadic and familial cases [ 207 ], meaning that the presence of such aggregates is widely regarded as a hallmark feature of ALS pathology. These deposits can occur in the cytoplasm of neurons [ 208 ] and skeletal muscle [ 99 , 209 ], and their presence is highly suggestive of an imbalance between protein synthesis and degradation pathways ( Figure 2 ).…”

Section: Impaired Protein Homeostasismentioning

confidence: 99%

Molecular and Cellular Mechanisms Affected in ALS

Gall

Anakor

Connolly

et al. 2020

JPM

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Amyotrophic lateral sclerosis (ALS) is a terminal late-onset condition characterized by the loss of upper and lower motor neurons. Mutations in more than 30 genes are associated to the disease, but these explain only ~20% of cases. The molecular functions of these genes implicate a wide range of cellular processes in ALS pathology, a cohesive understanding of which may provide clues to common molecular mechanisms across both familial (inherited) and sporadic cases and could be key to the development of effective therapeutic approaches. Here, the different pathways that have been investigated in ALS are summarized, discussing in detail: mitochondrial dysfunction, oxidative stress, axonal transport dysregulation, glutamate excitotoxicity, endosomal and vesicular transport impairment, impaired protein homeostasis, and aberrant RNA metabolism. This review considers the mechanistic roles of ALS-associated genes in pathology, viewed through the prism of shared molecular pathways.

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“…Like α-synuclein, SOD1 aggregation is assisted by fragmentation, both in cell-free and transgenic mouse models, and spreads through extracellular spaces [ 76–78 ]. There is growing evidence that relatively low molecular mass soluble species are the instigator of cell death and disease whereas large, insoluble aggregates are inert and possibly protective [ 79 , 80 ]. It may be, therefore, that disaggregation systems are an inadvertent source of hazardous, misfolded SOD1 oligomers ( Figure 2 ).…”

Section: Heat Shock Proteinsmentioning

confidence: 99%

Molecular and pharmacological chaperones for SOD1

Wright

2020

Biochemical Society Transactions

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The efficacy of superoxide dismutase-1 (SOD1) folding impacts neuronal loss in motor system neurodegenerative diseases. Mutations can prevent SOD1 post-translational processing leading to misfolding and cytoplasmic aggregation in familial amyotrophic lateral sclerosis (ALS). Evidence of immature, wild-type SOD1 misfolding has also been observed in sporadic ALS, non-SOD1 familial ALS and Parkinson's disease. The copper chaperone for SOD1 (hCCS) is a dedicated and specific chaperone that assists SOD1 folding and maturation to produce the active enzyme. Misfolded or misfolding prone SOD1 also interacts with heat shock proteins and macrophage migration inhibitory factor to aid folding, refolding or degradation. Recognition of specific SOD1 structures by the molecular chaperone network and timely dissociation of SOD1-chaperone complexes are, therefore, important steps in SOD1 processing. Harnessing these interactions for therapeutic benefit is actively pursued as is the modulation of SOD1 behaviour with pharmacological and peptide chaperones. This review highlights the structural and mechanistic aspects of a selection of SOD1-chaperone interactions together with their impact on disease models.

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SOD1-positive aggregate accumulation in the CNS predicts slower disease progression and increased longevity in a mutant SOD1 mouse model of ALS

Cited by 55 publications

References 51 publications

The biophysics of superoxide dismutase-1 and amyotrophic lateral sclerosis

The biophysics of superoxide dismutase-1 and amyotrophic lateral sclerosis

Molecular and Cellular Mechanisms Affected in ALS

Molecular and pharmacological chaperones for SOD1

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