superoxide dismutase-like immunoreactivity in Lewy body-like inclusions of sporadic amyotrophic lateral sclerosis

Shibata, Noriyuki; Hirano, Atsushi; Kobayashi, Makio; Sasaki, Shoichi; Kato, Takeshi; Matsumoto, Sadayuki; Shiozawa, Zenji; Komori, Takashi; Ikemoto, Akito; Umahara, Takahiko; Asayama, Kohtaro

doi:10.1016/0304-3940(94)90956-3

Cited by 136 publications

(85 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: 94%

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.

109

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: 94%

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.

109

146

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“…The exact composition of such inclusions, classified as "Lewy body-like inclusions", "Skein-like inclusions" (He and Hays, 2004;Kawashima et al, 1998), and Bunina bodies (Wada et al, 1999) is not known. However, the proteins identified so far can include ubiquitin (Leigh et al, 1991;Murayama et al, 1989), Cu/Zn superoxide dismutase 1 (SOD1) (Shibata et al, 1994(Shibata et al, , 1996, peripherin (He and Hays, 2004), Dorfin (a RING-finger type E3 ubiquitin ligase) (Niwa et al, 2002), and more rarely synuclein (Sone et al, 2005). Various studies conducted in ALS postmortem tissue in the early nineties found accumulations of intermediate filament proteins (hyperphosphorylated neurofilament subunits and peripherin) in hyaline conglomerate inclusions and axonal "spheroids" in spinal cord motoneurons (Corbo and Hays, 1992;Munoz et al, 1988;Sobue et al, 1990), and pyramidal cells of the motor cortex (Troost et al, 1992).…”

Section: Cellular and Molecular Pathogenesis Of Alsmentioning

confidence: 99%

Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis

Meethal

Atwood

2012

Neurobiology of Aging

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Amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease) is a progressive debilitating neurodegenerative disease with no cure. We propose a novel molecular model for the pathogenesis of ALS that involves an adenosine triphosphate (ATP)-dependent muscle neuronal lactate shuttle (MNLS) at the neuromuscular junction (NMJ) to regulate the flow of lactate from muscle to neurons and vice versa. Failure of the MNLS due to respiratory chain dysfunction is proposed to result in lactate toxicity and degeneration of nerve endings at the NMJ leading to nerve terminus dysjunction from the muscle cell. At a critical threshold where denervation outpaces reinnervation, a vicious cycle is established where the remaining innervated muscle fibers are required to work harder to compensate for normal function, and in so doing produce toxic lactate concentrations which induces further denervation and neuronal death. This mechanism explains the exponential progression of ALS leading to paralysis. The molecular events leading to the dysregulation of the MNLS and the dismantling of NMJ are explained in the context of known ALS familial mutations and age-related endocrine dyscrasia. Combination drug therapies that inhibit lactate accumulation at the NMJ, enhance respiratory chain function, and/or promote reinnervation are predicted to be effective therapeutic strategies for ALS. Published by Elsevier Inc.

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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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superoxide dismutase-like immunoreactivity in Lewy body-like inclusions of sporadic amyotrophic lateral sclerosis

Cited by 136 publications

References 13 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

Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis

Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis

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