Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells

Münch, Christian; O’Brien, John E.; Bertolotti, Anne

doi:10.1073/pnas.1017275108

Cited by 429 publications

(450 citation statements)

References 38 publications

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“…In people with SOD1-mediated familial ALS, mutant SOD1 protein may be a diagnostic or prognostic biomarker [48,49]. Misfolded SOD1 could potentially also be a target in sporadic ALS.…”

Section: Toward Novel Outcome Measures and Biomarkers In Als Trialsmentioning

confidence: 99%

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

2015

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The last 2 decades have seen a surge in the number of amyotrophic lateral sclerosis (ALS) clinical trials with the hope of finding successful treatments. Clinical trialists aim to repurpose existing drugs and test novel compounds to target potential ALS disease pathophysiology. Recent technological advancements have led to the discovery of new causative genetic agents and modes of delivering potential therapy, calling for increasingly sophisticated trial design. The standard ALS clinical trial design may be modified depending on study needs: type of therapy; route of therapy delivery; phase of therapy development; applicable subpopulation; market availability of therapy; and utility of telemedicine. Novel biomarkers of diagnostic, predictive, prognostic, and pharmacodynamic value are undergoing development and validation for use in clinical trials. Design modifications build on the traditional clinical trial design and may be employed in either the learning or confirming trial phase. Novel designs aim to minimize patient risk, study duration, and sample size, while improving efficiency and promoting statistical power to herald an exciting era for clinical research in ALS.

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“…In people with SOD1-mediated familial ALS, mutant SOD1 protein may be a diagnostic or prognostic biomarker [48,49]. Misfolded SOD1 could potentially also be a target in sporadic ALS.…”

Section: Toward Novel Outcome Measures and Biomarkers In Als Trialsmentioning

confidence: 99%

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

2015

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“…the intercellular transfer of misfolded proteins has recently been demonstrated in several neurodegenerative diseases, including aLS [1][2][3], and it has been suggested that this mechanism is responsible for the progressive spread of pathology. Mutations in SOD1 (Cu/Zn-superoxide dismutase) cause 20 % of familial aLS, and these cases display similar clinical features and pathogenesis to sporadic aLS, which accounts for 90 % of all aLS cases.…”

Section: Introductionmentioning

confidence: 99%

“…SOD1 is secreted by neuronal cells [12,13] and is present in the cerebrospinal fluid (CSF) of aLS patients [14,15]. aggregated mutant SOD1 can be taken up by cells via macropinocytosis which triggers subsequent aggregation of natively folded SOD1 [1]. Similarly, extracellular misfolded SOD1 Wt induces cell death [16] and overexpression of SOD1 Wt induces misfolding of natively folded SOD1 in human but not mouse neuronal cell lines, demonstrating species specificity in the transfer of misfolding [17].…”

Section: Introductionmentioning

confidence: 99%

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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“…In neural cells, SOD1 localized to endosomes after internalization, but could escape to induce native cytosolic SOD1 to aggregate. This templated misfolding persisted for at least a month, well after the original internalized aggregates were no longer detectable [77]. SOD1 seeds can also be found in the CSF of mice that over-express an aggregate-prone mutant form of the protein, and these seeds can induce new fibril formation of recombinant SOD1 in vitro [78].…”

Section: Spreading Pathology In Alsmentioning

confidence: 99%

“…Furthermore, it was recently observed that SOD1 fibrils can transfer between cells and be taken up via clathrinindependent macropinocytosis [77]. In neural cells, SOD1 localized to endosomes after internalization, but could escape to induce native cytosolic SOD1 to aggregate.…”

Section: Spreading Pathology In Alsmentioning

confidence: 99%

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

Kaufman

Diamond

2013

Neurotherapeutics

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Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells

Cited by 429 publications

References 38 publications

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

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

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

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