Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein

Desplats, Paula; Lee, He Jin; Bae, Eun Jin; Patrick, Christina; Rockenstein, Edward; Crews, Leslie; Spencer, Brian; Masliah, Eliezer; Lee, Seung-Jae

doi:10.1073/pnas.0903691106

Cited by 1,348 publications

(1,367 citation statements)

References 32 publications

(37 reference statements)

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“…In one case, neural stem cells were transplanted into transgenic mice expressing human α-synuclein. Human α-synuclein was detected in the grafted tissue as rapidly as 1 week after transplantation [33]. This was most consistent with α-synuclein transfer between neurons in vivo.…”

Section: Spread Of α-Synuclein Pathology To Young Neurons In Human Pasupporting

confidence: 72%

“…This concept was further tested in numerous rodent models using viral expression of human α-synclein [30,31] and transgenic mouse models of PD [32,33]. In one case, neural stem cells were transplanted into transgenic mice expressing human α-synuclein.…”

Section: Spread Of α-Synuclein Pathology To Young Neurons In Human Pamentioning

confidence: 99%

“…Conflicting data have been presented for tau, α-synuclein, and huntingtin peptides. α-synuclein uptake reportedly occurs via a temperature-sensitive mechanism that can be blocked by inhibiting endocytosis with a dominant negative dynamin mutant [32,33,64]. Proteinase K, which removes proteins from the extracellular surface, also abolishes the majority of α-synuclein uptake from the media [64].…”

Section: Uptake Of Aggregates Into Neuronsmentioning

confidence: 99%

“…This is consistent with a receptor-mediated mechanism. While the post-endocytic trafficking of α-synuclein is not yet clear, lysosomal inhibition with Bafilomycin A increases the levels of accumulated α-synuclein in the acceptor cell population [33,64]. Thus, the internalized α-synuclein may be degraded via lysosomes.…”

Section: Uptake Of Aggregates Into Neuronsmentioning

confidence: 99%

See 3 more Smart Citations

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

Kaufman

Diamond

2013

Neurotherapeutics

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Section: Spread Of α-Synuclein Pathology To Young Neurons In Human Pasupporting

confidence: 72%

Section: Spread Of α-Synuclein Pathology To Young Neurons In Human Pamentioning

confidence: 99%

Section: Uptake Of Aggregates Into Neuronsmentioning

confidence: 99%

Section: Uptake Of Aggregates Into Neuronsmentioning

confidence: 99%

See 2 more Smart Citations

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

Kaufman

Diamond

2013

Neurotherapeutics

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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%

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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Conformation-Specific Detection of α-Synuclein

Bartels

2017

JAMA Neurol

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The way protein misfolding and aggregation has been studied in the field of Parkinson disease (PD) has undergone some major changes in the past 20 years. After the initial discovery of α-synuclein (αSyn) aggregates as the main component of the Lewy body, the pathologic hallmark of PD, 1 the involvement of small, soluble αSyn aggregates as the putative culprit of neurotoxic effects quickly became one of the major research directions for understanding the mechanism of neurodegeneration in PD. The mechanistic studies have been challenging, however, mainly because of the complex folding behavior of αSyn. The challenges have been 2-fold. Although in vivo and cell culture models struggled with recapitulating amyloid aggregation and Lewy body formation that would mimic the neurodegeneration and protein deposits observed in patients, the in vitro studies based on recombinantly expressed protein faced the opposite problem. Although synthetic protein readily forms amyloid fibrils akin to Lewy bodies in the test tube, the exact structure and biological activity of these aggregates have been polymorphic, meaning that they highly depend on the exact in vitro conditions used for preparation. Various forms and shapes with equally diverse methods of action have emerged in the literature, but reproducibility between laboratories has been an issue, mainly owing to the specific aggregation protocols used to synthesize these species. This lack of reproducibility made it difficult to relate specific forms to those that might develop in the context of a patient's brain.In terms of suitable in vivo models, a major breakthrough came recently in several studies that used exogenous application of preaggregated fibrils in model systems. Based on earlier studies that seemed to indicate a progression of the pathologic aggregation process throughout the brain, 2-4 several laboratories applied exogenous αSyn fibrils to a range of cellular or mouse models and saw an impressive recapitulation of the human disease. 5,6 These studies did not only mean a major advance in terms of methodology for studying αSyn aggregation in living systems, but also suggested that αSynmediated pathology spreads in the human body akin to prion diseases. However, the exact method of preparing these synthetic species greatly influences their bioactivity, 7 raising again the specter of the in vivo relevance of these species and their association with the pathomechanism in PD. 8 Testing for the presence of these species in biological samples as a validation for their importance has been challenging for a variety of reasons. Given the often limited availability of patient samples and the typically low amount of αSyn in relevant fluids (eg, cerebrospinal fluid), the assay in question should be able to test the principal nature of αSyn (ie, pathologic vs physiologic) in complex biofluids with high specificity and sensitivity. The most common solution to this prob-

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Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein

Cited by 1,348 publications

References 32 publications

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

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

Conformation-Specific Detection of α-Synuclein

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