The Golgi apparatus of spinal cord motor neurons in transgenic mice expressing mutant Cu,Zn superoxide dismutase becomes fragmented in early, preclinical stages of the disease.

Mourelatos, Zissimos P.; Gonatas, Nicholas K.; Stieber, Anna; Gurney, Mark E.; Canto, Mauro C. Dal

doi:10.1073/pnas.93.11.5472

Cited by 215 publications

(210 citation statements)

References 41 publications

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“…Mutant SOD1 induces eR stress [6] and Golgi fragmentation [26] in neuronal cell cultures, and we now show that aggregated SOD1 Wt induces UPR and Golgi fragmentation similar to mutant SOD1. these findings are consistent with recent evidence for common pathogenic pathways shared by mutant SOD1 and SOD1 Wt , and the presence of misfolded SOD1 Wt in sporadic aLS tissues [4,5].…”

Section: Discussionsupporting

confidence: 59%

“…We also confirm here that intracellular mutant SOD1 inhibits the transport of VSVG-ts045 from the eR to Golgi in Sh-SY5Y cells, and we show that extracellular forms of mutant and aggregated SOD1 Wt also delay eR-Golgi traffic, thus providing one possible explanation for induction of eR stress. Similarly, Golgi fragmentation is also triggered by an imbalance between anterograde and retrograde traffic between eR and Golgi [26], highlighting a possible role for disruption to eR-Golgi traffic in both events. the activation of pro-apoptotic ChOP and increase in the proportion of cells undergoing apoptosis in cells treated with extracellular SOD1 provides a link between extracellular proteins and neurodegeneration and UPR-specific cell death.…”

Section: Discussionmentioning

confidence: 99%

“…however, eR stress can also be triggered by inhibition of protein transport between eR and Golgi apparatus [24,25]. Inhibition of eR-Golgi transport implies disruption to the secretory pathway, and Golgi fragmentation is another pathological feature of aLS, observed in both human patients and cellular and animal disease models [9,26]. Likewise, the Golgi apparatus can fragment due to defects in eR to Golgi trafficking [27].…”

Section: Introductionmentioning

confidence: 99%

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Extracellular wildtype and mutant SOD1 induces ER–Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells

Sundaramoorthy

Walker

Yerbury

et al. 2013

Cell. Mol. Life Sci.

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Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disorder and the majority of ALS is sporadic, where misfolding and aggregation of Cu/Zn-superoxide dismutase (SOD1) is a feature shared with familial mutant-SOD1 cases. ALS is characterized by progressive neurospatial spread of pathology among motor neurons, and recently the transfer of extracellular, aggregated mutant SOD1 between cells was demonstrated in culture. However, there is currently no evidence that uptake of SOD1 into cells initiates neurodegenerative pathways reminiscent of ALS pathology. Similarly, whilst dysfunction to the ERGolgi compartments is increasingly implicated in the pathogenesis of both sporadic and familial ALS, it remains unclear whether misfolded, wildtype SOD1 triggers ER-Golgi dysfunction. In this study we show that both extracellular, native wildtype and mutant SOD1 are taken up by macropinocytosis into neuronal cells. Hence uptake does not depend on SOD1 mutation or misfolding. We also demonstrate that purified mutant SOD1 added exogenously to neuronal cells inhibits protein transport between the ER-Golgi apparatus, leading to Golgi fragmentation, induction of ER stress and apoptotic cell death. Furthermore, we show that extracellular, aggregated, wildtype SOD1 also induces ER-Golgi pathology similar to mutant SOD1, leading to apoptotic cell death. Hence extracellular misfolded wildtype or mutant SOD1 induce dysfunction to ERGolgi compartments characteristic of ALS in neuronal cells, implicating extracellular SOD1 in the spread of pathology among motor neurons in both sporadic and familial ALS. Abstract amyotrophic lateral sclerosis (aLS) is a fatal and rapidly progressing neurodegenerative disorder and the majority of aLS is sporadic, where misfolding and aggregation of Cu/Zn-superoxide dismutase (SOD1) is a feature shared with familial mutant-SOD1 cases. aLS is characterized by progressive neurospatial spread of pathology among motor neurons, and recently the transfer of extracellular, aggregated mutant SOD1 between cells was demonstrated in culture. however, there is currently no evidence that uptake of SOD1 into cells initiates neurodegenerative pathways reminiscent of aLS pathology. Similarly, whilst dysfunction to the eR-Golgi compartments is increasingly implicated in the pathogenesis of both sporadic and familial aLS, it remains unclear whether misfolded, wildtype SOD1 triggers eR-Golgi dysfunction. In this study we show that both extracellular, native wildtype and mutant SOD1 are taken up by macropinocytosis into neuronal cells. hence uptake does not depend on SOD1 mutation or misfolding. We also demonstrate that purified mutant SOD1 added exogenously to neuronal cells inhibits protein transport between the eR-Golgi apparatus, leading to Golgi fragmentation, induction of eR stress and apoptotic cell death. Furthermore, we show that extracellular, aggregated, wildtype SOD1 also induces eR-Golgi pathology similar to mutant SOD1, leading to apoptotic cell death. hence extracellu...

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Extracellular wildtype and mutant SOD1 induces ER–Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells

Sundaramoorthy

Walker

Yerbury

et al. 2013

Cell. Mol. Life Sci.

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“…Mutated Cu,Zn-SOD have several enhanced activities that could be capable of selectively damaging interacting proteins or their associated organelles (5,24,36,38). Investigators at our laboratory previously reported that Cu-binding affinities are decreased in mutated Cu,Zn-SOD (26) and mutated Cu,Zn-SOD are highly susceptible to nonenzymatic glycosylation, i.e., glycation (34).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of mutated Cu,Zn-SOD in neuroblastoma cells results in cytoskeletal change

Takamiya

Takahashi²,

Park³

et al. 2005

American Journal of Physiology-Cell Physiology

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Amyotrophic lateral sclerosis (ALS) involves the progressive degeneration of motor neurons in the spinal cord and the motor cortex. It has been shown that 15–20% of patients with familial ALS (FALS) have defects in the Sod1 gene, which encodes Cu,Zn-superoxide dismutase (SOD). To elucidate the pathological role of mutated Cu,Zn-SOD, we examined the issue of whether mutated Cu,Zn-SOD affects the cell cycle. Mouse neuroblastoma Neuro-2a cells were transfected with human wild-type or mutated (G37R, G93A) Cu,Zn-SOD. Mutated, Cu,Zn-SOD-transfected cells exhibited marked retardation in cell growth and G2/M arrest. They also displayed lower reactivity to phalloidin, indicating that the cytoskeleton was disrupted. Immunoprecipitation, two-dimensional gel electrophoresis, and Western blot analysis indicated that mutated Cu,Zn-SOD associates with actin. Similar results were obtained by in vitro incubation experiments with purified actin and mutated Cu,Zn-SOD (G93A). These results suggest that mutated Cu,Zn-SOD in FALS causes cytoskeletal changes by associating with actin, which subsequently causes G2/M arrest and growth retardation.

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“…1 A Lower). Because there is evidence for early commencing noxious effects of mutant hSOD1s in spinal cords (7,(10)(11)(12), the G93A transgenic mice were examined from birth until death. The high proportion (Ϸ3%) of HIC-binding hSOD1 in spinal cord was seen from birth throughout life.…”

Section: The Hic-binding Hsod1 Is Enriched In the Spinal Cords In Thementioning

confidence: 99%

Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS models

Zetterström

Stewart

Bergemalm

et al. 2007

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

144

156

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Mutants of superoxide dismutase-1 (SOD1) cause ALS by an unidentified cytotoxic mechanism. We have previously shown that the stable SOD1 mutants D90A and G93A are abundant and show the highest levels in liver and kidney in transgenic murine ALS models, whereas the unstable G85R and G127X mutants are scarce but enriched in the CNS. These data indicated that minute amounts of misfolded SOD1 enriched in the motor areas might exert the ALS-causing cytotoxicity. A hydrophobic interaction chromatography (HIC) protocol was developed with the aim to determine the abundance of soluble misfolded SOD1 in tissues in vivo. Most G85R and G127X mutant SOD1s bound in the assay, but only minute subfractions of the D90A and G93A mutants. The absolute levels of HIC-binding SOD1 were, however, similar and broadly inversely related to lifespans in the models. They were generally enriched in the susceptible spinal cord. The HIC-binding SOD1 was composed of disulfide-reduced subunits lacking metal ions and also subunits that apparently carried nonnative intrasubunit disulfide bonds. The levels were high from birth until death and were comparable to the amounts of SOD1 that become sequestered in aggregates in the terminal stage. The HIC-binding SOD1 species ranged from monomeric to trimeric in size. These species form a least common denominator amongst SOD1 mutants with widely different molecular characteristics and might be involved in the cytotoxicity that causes ALS.disulfide bond ͉ motor neuron ͉ neurodegeneration A myotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration, resulting in progressive paralysis, and death from respiratory failure. Approximately 10% of ALS cases are familial (1) and in some of these the disease is linked to mutations in the CuZn-superoxide dismutase (SOD1) gene (2). Overall, Ϸ6% of all cases with ALS show SOD1 mutations, and more than 100 different such mutations have been identified (3). The mutations confer a cytotoxic gain of function to the enzyme (4, 5). SOD1 is ubiquitously expressed, and in several organs at higher levels than in the motor areas in the CNS (6, 7). Both the nature of the cytotoxicity, and the reasons for the particular susceptibility of some parts of the CNS remain unexplained.It is likely that the different mutant SOD1s cause ALS by essentially the same mechanism. Still, the levels of different mutant SOD1s in the human CNS differ by more than 200-fold (7). Similar large differences are observed in the murine ALS models. In spinal cords from mice expressing the D90A, G93A, G85R and G127insTGGG (G127X) mutant human SOD1s (hSOD1s), the levels are 20, 14, 0.9, and 0.45 times as large, respectively, as the levels of the endogenous murine SOD1 (mSOD1) (8). In the high-level models, D90A and G93A, most hSOD1 lacks enzymatic activity owing to Cu-deficiency, and significant proportions lack the stabilizing intrasubunit disulfide bond. The G85R and G127X hSOD1s lack both enzymatic activity and the disulfide bond. Whereas the liver and kidney contain the highest lev...

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The Golgi apparatus of spinal cord motor neurons in transgenic mice expressing mutant Cu,Zn superoxide dismutase becomes fragmented in early, preclinical stages of the disease.

Cited by 215 publications

References 41 publications

Extracellular wildtype and mutant SOD1 induces ER–Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells

Extracellular wildtype and mutant SOD1 induces ER–Golgi pathology characteristic of amyotrophic lateral sclerosis in neuronal cells

Overexpression of mutated Cu,Zn-SOD in neuroblastoma cells results in cytoskeletal change

Soluble misfolded subfractions of mutant superoxide dismutase-1s are enriched in spinal cords throughout life in murine ALS models

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