Progressive Aggregation of Alpha-Synuclein and Selective Degeneration of Lewy Inclusion-Bearing Neurons in a Mouse Model of Parkinsonism

Osterberg, Valerie R.; Spinelli, Kateri J.; Weston, Leah J.; Luk, Kelvin C.; Woltjer, Randall L.; Unni, Vivek K.

doi:10.1016/j.celrep.2015.01.060

Cited by 198 publications

(252 citation statements)

References 37 publications

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“…The numbers of aggregates required for ROS production are therefore two orders of magnitude lower than what is required for the templated seeding, and this difference suggests that the templated seeding by the oligomers occurs less readily than the cellular damage caused by the aggregates themselves. This idea is consistent with the long-established link between oxidative stress and neurodegeneration (49) and the fact that the oxidative reactions can promote the aggregation of αS (50), and it is corroborated by experimentally observed correlation between αS seeding and cellular toxicity (15). Based on our findings, we hypothesize that for small aggregates in vivo, if templated seeding occurs, it is under conditions of raised levels of ROS, which in turn may promote αS aggregation, resulting in the aggregate spreading in a cell-driven way that does not strongly depend on the seeding effectiveness, as illustrated in Fig.…”

Section: Discussionsupporting

confidence: 72%

“…Furthermore, transplanted embryonic neurons in patients with PD developed LB deposits, suggesting that these aggregates can spread (11). Experiments in wild-type and transgenic mice showed that injection of fibrils of recombinant αS could lead to the aggregation of the endogenous protein, supporting this concept (12)(13)(14), and the selective fate of the aggregate-containing neurons was demonstrated (15). Although the pathological spreading of αS has now been reproduced in many laboratories, the molecular mechanism of the observed phenomenon is not fully understood and this is important for rational development of therapies.…”

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confidence: 56%

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Kinetic model of the aggregation of alpha-synuclein provides insights into prion-like spreading

Iljina

Garcia

Horrocks

et al. 2016

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

198

254

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The protein alpha-synuclein (αS) self-assembles into small oligomeric species and subsequently into amyloid fibrils that accumulate and proliferate during the development of Parkinson's disease. However, the quantitative characterization of the aggregation and spreading of αS remains challenging to achieve. Previously, we identified a conformational conversion step leading from the initially formed oligomers to more compact oligomers preceding fibril formation. Here, by a combination of single-molecule fluorescence measurements and kinetic analysis, we find that the reaction in solution involves two unimolecular structural conversion steps, from the disordered to more compact oligomers and then to fibrils, which can elongate by further monomer addition. We have obtained individual rate constants for these key microscopic steps by applying a global kinetic analysis to both the decrease in the concentration of monomeric protein molecules and the increase in oligomer concentrations over a 0.5-140-μM range of αS. The resulting explicit kinetic model of αS aggregation has been used to quantitatively explore seeding the reaction by either the compact oligomers or fibrils. Our predictions reveal that, although fibrils are more effective at seeding than oligomers, very high numbers of seeds of either type, of the order of 10 4 , are required to achieve efficient seeding and bypass the slow generation of aggregates through primary nucleation. Complementary cellular experiments demonstrated that two orders of magnitude lower numbers of oligomers were sufficient to generate high levels of reactive oxygen species, suggesting that effective templated seeding is likely to require both the presence of template aggregates and conditions of cellular stress.amyloid aggregation | kinetic analysis | templated seeding | prion-like propagation | neurodegeneration

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Section: Discussionsupporting

confidence: 72%

mentioning

confidence: 56%

Kinetic model of the aggregation of alpha-synuclein provides insights into prion-like spreading

Iljina

Garcia

Horrocks

et al. 2016

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

198

254

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“…The inclusions formed could be classified depending on their localization in the cell. Neuritic and perykarial inclusions have also been observed by others (49,51,57) and colocalize with Hsp90, resembling pathology-related aggregates (40). These inclusions are formed by both endogenous aSyn and internalized recombinant species.…”

Section: Discussionmentioning

confidence: 74%

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Villar‐Piqué

Fonseca

Sant’Anna

et al. 2016

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

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Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of α-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors. Here, we analyzed these factors and found that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q aSyn mutation induces a significant alteration in the aggregation properties of aSyn. We compared the aggregation of WT and H50Q aSyn with and without copper, and assessed the effects of the resultant protein species when applied to primary neuronal cultures. The presence of copper induces the formation of structurally different and less-damaging aSyn aggregates. Interestingly, these aggregates exhibit a stronger capacity to induce aSyn inclusion formation in recipient cells, which demonstrates that the structural features of aSyn species determine their effect in neuronal cells and supports a lack of correlation between toxicity and inclusion formation. In total, our study provides strong support in favor of the hypothesis that protein aggregation is not a primary cause of cytotoxicity.α-synuclein | copper | H50Q mutation | inclusions | protein aggregation

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“…Cite this article as Cold Spring Harb Perspect Biol 2017;9:a023523 recent article that describes long-term surveillance of deposition sites containing aggregated a-synuclein indicated that over time these deposits are associated with cell death (Osterberg et al 2015). This apparent contradiction can be explained by at least two models.…”

Section: Protein Quality Control In Health and Diseasementioning

confidence: 89%

Protein Quality Control in Health and Disease

Dubnikov

Ben‐Gedalya

Cohen

2016

Cold Spring Harb Perspect Biol

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Maintaining functional protein homeostasis ( proteostasis) is a constant challenge in the face of limited protein-folding capacity, environmental threats, and aging. Cells have developed several quality-control mechanisms that assist nascent polypeptides to fold properly, clear misfolded molecules, respond to the accumulation of protein aggregates, and deposit potentially toxic conformers in designated sites. Proteostasis collapse can lead to the development of diseases known as proteinopathies. Here we delineate the current knowledge on the different layers of protein quality-control mechanisms at the organelle and cellular levels with an emphasis on the prion protein (PrP). We also describe how protein quality control is integrated at the organismal level and discuss future perspectives on utilizing proteostasis maintenance as a strategy to develop novel therapies for the treatment of proteinopathies.

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Progressive Aggregation of Alpha-Synuclein and Selective Degeneration of Lewy Inclusion-Bearing Neurons in a Mouse Model of Parkinsonism

Cited by 198 publications

References 37 publications

Kinetic model of the aggregation of alpha-synuclein provides insights into prion-like spreading

Kinetic model of the aggregation of alpha-synuclein provides insights into prion-like spreading

Environmental and genetic factors support the dissociation between α-synuclein aggregation and toxicity

Protein Quality Control in Health and Disease

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