Unfolding the role of protein misfolding in neurodegenerative diseases

Soto, Claudio

doi:10.1038/nrn1007

Cited by 1,297 publications

(1,106 citation statements)

References 146 publications

Supporting

Mentioning

1,076

Contrasting

Unclassified

Order By: Relevance

“…Each intensity burst represents the binding of the imaging strand to the aptamer. Grey: raw intensity profile, blue: using a Chung–Kennedy filter31 with a window of five frames applied. D) Examples of diffraction‐limited (DL, using thioflavin‐T) and super‐resolved (using ADPAINT) images of an αS and Aβ oligomer and fibril.…”

mentioning

confidence: 99%

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells

et al. 2018

View full text Add to dashboard Cite

The aberrant misfolding and subsequent conversion of monomeric protein into amyloid aggregates characterises many neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. These aggregates are highly heterogeneous in structure, generally of low abundance and typically smaller than the diffraction limit of light (≈250 nm). To overcome the challenges these characteristics pose to the study of endogenous aggregates formed in cells, we have developed a method to characterise them at the nanometre scale without the need for a conjugated fluorophore. Using a combination of DNA PAINT and an amyloid‐specific aptamer, we demonstrate that this technique is able to detect and super‐resolve a range of aggregated species, including those formed by α‐synuclein and amyloid‐β. Additionally, this method enables endogenous protein aggregates within cells to be characterised. We found that neuronal cells derived from patients with Parkinson's disease contain a larger number of protein aggregates than those from healthy controls.

show abstract

mentioning

confidence: 99%

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells

et al. 2018

View full text Add to dashboard Cite

show abstract

“…The conversion of soluble proteins into fibrillar amyloid deposits is a hallmark of a range of increasingly prevalent neurodegenerative disorders including Alzheimer's Disease (AD) and Parkinson Disease (PD) 1, 2, 3, 4. It has been reported that the species formed during the aggregation reactions have a toxic effect on cells 5, 6, 7, 8.…”

mentioning

confidence: 99%

“…It has been reported that the species formed during the aggregation reactions have a toxic effect on cells 5, 6, 7, 8. Several possible mechanisms of cellular damage have been identified with relative contributions that depend on both the concentrations and the types of aggregates present 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11. The aggregation process that results in the formation of oligomers may contribute to cellular damage 12, 13, 14, 15.…”

mentioning

confidence: 99%

“…The aggregation process that results in the formation of oligomers may contribute to cellular damage 12, 13, 14, 15. Some of these mechanisms are thought to involve specific binding to receptors on the cell membrane1, 5, 9 while others appear to be the consequence of non‐specific membrane disruption 1, 3, 5, 9, 16. A body of data suggests that small soluble aggregates, often called oligomers, rather than mature fibrils, are able to cause the membrane to become permeable to Ca 2+ resulting in Ca 2+ influx and the disruption of Ca 2+ homeostasis 2, 3, 5, 9, 17, 18.…”

mentioning

confidence: 99%

“…Therefore, it is important to quantify and characterize these species within aggregation mixtures in vitro as well as to be able to perform measurements in biological samples, such as cerebrospinal fluid (CSF) 19. However, these oligomers are known to be present at low abundance and to be highly heterogeneous in nature, in terms of both their size and structure 1, 2, 3, 4, 9, 10, 16…”

mentioning

confidence: 99%

See 2 more Smart Citations

Ultrasensitive Measurement of Ca²⁺ Influx into Lipid Vesicles Induced by Protein Aggregates

Flagmeier

Wirthensohn

et al. 2017

Angew Chem Int Ed

View full text Add to dashboard Cite

To quantify and characterize the potentially toxic protein aggregates associated with neurodegenerative diseases, a high‐throughput assay based on measuring the extent of aggregate‐induced Ca2+ entry into individual lipid vesicles has been developed. This approach was implemented by tethering vesicles containing a Ca2+ sensitive fluorescent dye to a passivated surface and measuring changes in the fluorescence as a result of membrane disruption using total internal reflection microscopy. Picomolar concentrations of Aβ42 oligomers could be observed to induce Ca2+ influx, which could be inhibited by the addition of a naturally occurring chaperone and a nanobody designed to bind to the Aβ peptide. We show that the assay can be used to study aggregates from other proteins, such as α‐synuclein, and to probe the effects of complex biofluids, such as cerebrospinal fluid, and thus has wide applicability.

show abstract

Protein Misfolding and Neurodegeneration

Soto¹,

Estrada²

2008

Arch Neurol

Self Cite

299

202

View full text Add to dashboard Cite

key molecular pathway implicated in diverse neurodegenerative diseases is the misfolding, aggregation, and accumulation of proteins in the brain. Compelling evidence strongly supports the hypothesis that accumulation of misfolded proteins leads to synaptic dysfunction, neuronal apoptosis, brain damage, and disease. However, the mechanism by which protein misfolding and aggregation trigger neurodegeneration and the identity of the neurotoxic structure is still unclear. The aim of this article is to review the literature around the molecular mechanism and role of misfolded protein aggregates in neurodegeneration and the potential for the misfolding process to lead to a transmissible form of disease by a prion-based model of propagation.

show abstract

Unfolding the role of protein misfolding in neurodegenerative diseases

Cited by 1,297 publications

References 146 publications

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells

Ultrasensitive Measurement of Ca²⁺ Influx into Lipid Vesicles Induced by Protein Aggregates

Protein Misfolding and Neurodegeneration

Contact Info

Product

Resources

About

Unfolding the role of protein misfolding in neurodegenerative diseases

Cited by 1,297 publications

References 146 publications

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells

Nanoscopic Characterisation of Individual Endogenous Protein Aggregates in Human Neuronal Cells

Ultrasensitive Measurement of Ca2+ Influx into Lipid Vesicles Induced by Protein Aggregates

Protein Misfolding and Neurodegeneration

Contact Info

Product

Resources

About

Ultrasensitive Measurement of Ca²⁺ Influx into Lipid Vesicles Induced by Protein Aggregates