Common molecular signature in SOD1 for both sporadic and familial amyotrophic lateral sclerosis

Gruzman, Arie; Wood, William L.; Alpert, Evgenia; Prasad, M. Dharma; Miller, Robert G.; Rothstein, Jeffery D.; Bowser, Robert; Hamilton, Ronald L.; Wood, Troy D.; Cleveland, Don W.; Lingappa, Vishwanath R.; Liu, Jian

doi:10.1073/pnas.0705044104

Cited by 173 publications

(140 citation statements)

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“…Given that SOD1 has been shown to undergo aberrant aggregation in both familial and sporadic ALS (35)(36)(37), we propose that formation of SOD1 trimer is a common pathogenic mechanism in ALS, causing the death of motor neurons and progression of the disease. At the time of writing, 62% of residues known to feature disease-relevant point mutations are located in the proposed SOD1 trimer interfaces (Table S1 and Dataset S1).…”

Section: Discussionmentioning

confidence: 99%

Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis

Proctor

Fee

Tao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

146

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Since the linking of mutations in the Cu,Zn superoxide dismutase gene (sod1) to amyotrophic lateral sclerosis (ALS) in 1993, researchers have sought the connection between SOD1 and motor neuron death. Disease-linked mutations tend to destabilize the native dimeric structure of SOD1, and plaques containing misfolded and aggregated SOD1 have been found in the motor neurons of patients with ALS. Despite advances in understanding of ALS disease progression and SOD1 folding and stability, cytotoxic species and mechanisms remain unknown, greatly impeding the search for and design of therapeutic interventions. Here, we definitively link cytotoxicity associated with SOD1 aggregation in ALS to a nonnative trimeric SOD1 species. We develop methodology for the incorporation of low-resolution experimental data into simulations toward the structural modeling of metastable, multidomain aggregation intermediates. We apply this methodology to derive the structure of a SOD1 trimer, which we validate in vitro and in hybridized motor neurons. We show that SOD1 mutants designed to promote trimerization increase cell death. Further, we demonstrate that the cytotoxicity of the designed mutants correlates with trimer stability, providing a direct link between the presence of misfolded oligomers and neuron death. Identification of cytotoxic species is the first and critical step in elucidating the molecular etiology of ALS, and the ability to manipulate formation of these species will provide an avenue for the development of future therapeutic strategies.neurodegeneration | protein aggregation | protein misfolding | ALS | structural modeling P rotein misfolding and aggregation are linked to cell death and disease progression in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). In these diseases and others, the formation of amyloid plaques, often observed post mortem, has long been thought to play a role in neurodegeneration, but toxicity has never been confirmed (1-3). Recent research has shown that small, soluble oligomers, rather than insoluble amyloids, are likely to be the cytotoxic species causing neurodegeneration (4-14). These small, soluble oligomers undergo aberrant interactions with cell machinery and activate cell death pathways, but their exact stoichiometry is not known and their properties have yet to be characterized. Recently, metastable soluble Cu,Zn superoxide dismutase (SOD1) oligomers have been identified that contain an epitope associated with disease-linked species of SOD1, mutants of which are implicated in a subset of ALS (15-18). Size exclusion chromatography (SEC) of these oligomers revealed a size range of two to four monomers, consistent with previous findings of potentially cytotoxic SOD1 oligomers (19)(20)(21).Knowledge of the structures of these species would not only allow for definitive testing of their toxicity but could potentially lead to an understanding of disease mechanism and therapeutic strategies against diseases for which no ...

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Section: Discussionmentioning

confidence: 99%

Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis

Proctor

Fee

Tao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

146

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“…Our model implies that WT SOD1 also is able to form oligomers, although with decreased probability. This inherent feature explains the observations that WT SOD1 can oligomerize or aggregate (11,15,16), that inclusions of WT SOD1 have been identified in patients with sporadic ALS (7), and that WT SOD1 exacerbates disease in double-transgenic mice (44). The initial misfolding transition of SOD1 might serve as a target for intervention of SOD1-associated cytotoxicity in ALS.…”

Section: Biophysics and Computational Biologymentioning

confidence: 99%

“…The prevailing hypothesis, based on the accumulation of insoluble protein deposits in motor neurons, asserts that pathogenesis involves protein misfolding and aggregation (1,2). Mounting evidence indicates that the gain of toxic function in SOD1-linked ALS, as in many other misfolding diseases, is caused by molecular species that arise early in the aggregation process as opposed to the macroscopic deposits per se (5)(6)(7)(8). The structural events triggering oligomerization have remained enigmatic, however, as is the case in other protein-misfolding diseases (9).…”

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confidence: 99%

Transient structural distortion of metal-free Cu/Zn superoxide dismutase triggers aberrant oligomerization

Teilum

Smith

Schulz

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease linked to the misfolding of Cu/Zn superoxide dismutase (SOD1).ALS-related defects in SOD1 result in a gain of toxic function that coincides with aberrant oligomerization. The structural events triggering oligomerization have remained enigmatic, however, as is the case in other protein-misfolding diseases. Here, we target the critical conformational change that defines the earliest step toward aggregation. Using nuclear spin relaxation dispersion experiments, we identified a short-lived (0.4 ms) and weakly populated (0.7%) conformation of metal-depleted SOD1 that triggers aberrant oligomerization. This excited state emanates from the folded ground state and is suppressed by metal binding, but is present in both the disulfide-oxidized and disulfide-reduced forms of the protein. Our results pinpoint a perturbed region of the excited-state structure that forms intermolecular contacts in the earliest nonnative dimer/ oligomer. The conformational transition that triggers oligomerization is a common feature of WT SOD1 and ALS-associated mutants that have widely different physicochemical properties. But compared with WT SOD1, the mutants have enhanced structural distortions in their excited states, and in some cases slightly higher excited-state populations and lower kinetic barriers, implying increased susceptibility to oligomerization. Our results provide a unified picture that highlights both (i) a common denominator among different SOD1 variants that may explain why diverse mutations cause the same disease, and (ii) a structural basis that may aid in understanding how different mutations affect disease propensity and progression.amyotrophic lateral sclerosis ͉ nuclear magnetic resonance relaxation ͉ protein misfolding

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“…Postmortem examination of ALS patient tissues reveals an obvious loss of motor neurons in the central nervous system (CNS), while many remaining neurons demonstrate central chromatolysis, numerous inclusions, swelling of the perikaryon and proximal axon, mitochondria swellings, vacuoles, and neurofilament accumulations [26]. Intracellular inclusions of ubiquitinated misfolded proteins, including transactive response DNA binding protein 43 kDa, SOD1, phosphorylated neurofiliaments, fused in sarcoma, and/or cystatin C occur in both hereditary and nonhereditary cases, and are a pathologic hallmark of disease [27][28][29][30][31][32]. The processes involved in motor neuron injury can be further categorized into mechanisms that are "cell autonomous" occurring within the motor neuron, and "noncell autonomous" involving multiple non-neuronal cells contributing to the disease process [33].…”

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confidence: 99%

Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis

et al. 2015

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Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disorder characterized by loss of motor neurons, resulting in paralysis and death. Multiple mechanisms of motor neuron injury have been implicated based upon the more than 20 different genetic causes of familial ALS. These inherited mutations compromise diverse motor neuron pathways leading to cell-autonomous injury. In the ALS transgenic mouse models, however, motor neurons do not die alone. Cell death is noncell-autonomous dependent upon a well orchestrated dialogue between motor neurons and surrounding glia and adaptive immune cells. The pathogenesis of ALS consists of 2 stages: an early neuroprotective stage and a later neurotoxic stage. During early phases of disease progression, the immune system is protective with glia and T cells, especially M2 macrophages/microglia, and T helper 2 cells and regulatory T cells, providing anti-inflammatory factors that sustain motor neuron viability. As the disease progresses and motor neuron injury accelerates, a second rapidly progressing phase develops, characterized by M1 macrophages/microglia, and proinflammatory T cells. In rapidly progressing ALS patients, as in transgenic mice, neuroprotective regulatory T cells are significantly decreased and neurotoxicity predominates. Our own therapeutic efforts are focused on modulating these neuroinflammatory pathways. This review will focus on the cellular players involved in neuroinflammation in ALS and current therapeutic strategies to enhance neuroprotection and suppress neurotoxicity with the goal of arresting the progressive and devastating nature of ALS.

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Common molecular signature in SOD1 for both sporadic and familial amyotrophic lateral sclerosis

Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating motor neuroncopper, zinc superoxide dismutase ͉ motor neuron ͉ neurodegeneration

Cited by 173 publications

References 36 publications

Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis

Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis

Transient structural distortion of metal-free Cu/Zn superoxide dismutase triggers aberrant oligomerization

Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis

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