Molecular mechanisms of amyloid formation in living systems

Sinnige, Tessa

doi:10.1039/d2sc01278b

Cited by 39 publications

(26 citation statements)

References 187 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In perspective, Mass Spectrometry Imaging (MSI), a technique where an ion or a laser beam is raster scanned over the tissue surface to vaporize it into molecules that are then immediately transferred to the mass spectrometer, has the potential to go beyond shotgun proteomics in amyloid typing ( 85 , 86 ) thanks to its ability to preserve spatial distribution of proteins in tissues and therefore allow direct observation of the molecular composition of amyloid deposits ( 87 ). In addition, the MSI approach can permit direct localization of other types of biomolecule, such as lipids ( 88 ) or metabolites in bioptic specimens ( 89 ), and could provide new insights into the process of fibrillar protein aggregation, today still largely misunderstood ( 90 ).…”

Section: Typing Amyloidmentioning

confidence: 99%

Amyloidosis: What does pathology offer? The evolving field of tissue biopsy

Riefolo

Conti

Longhi

et al. 2022

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Since the mid-nineteenth century pathology has followed the convoluted story of amyloidosis, recognized its morphology in tissues and made identification possible using specific staining. Since then, pathology studies have made a significant contribution and advanced knowledge of the disease, so providing valuable information on the pathophysiology of amyloid aggregation and opening the way to clinical studies and non-invasive diagnostic techniques. As amyloidosis is a heterogeneous disease with various organ and tissue deposition patterns, histology evaluation, far from offering a simple yes/no indication of amyloid presence, can provide a wide spectrum of qualitative and quantitative information related to and changing with the etiology of the disease, the comorbidities and the clinical characteristics of patients. With the exception of cardiac transthyretin related amyloidosis cases, which today can be diagnosed using non-biopsy algorithms when stringent clinical criteria are met, tissue biopsy is still an essential tool for a definitive diagnosis in doubtful cases and also to define etiology by typing amyloid fibrils. This review describes the histologic approach to amyloidosis today and the current role of tissue screening biopsy or targeted organ biopsy protocols in the light of present diagnostic algorithms and various clinical situations, with particular focus on endomyocardial and renal biopsies. Special attention is given to techniques for typing amyloid fibril proteins, necessary for the new therapies available today for cardiac transthyretin related amyloidosis and to avoid patients receiving inappropriate chemotherapy in presence of plasma cell dyscrasia unrelated to amyloidosis. As the disease is still burdened with high mortality, the role of tissue biopsy in early diagnosis to assure prompt treatment is also mentioned.

show abstract

Section: Typing Amyloidmentioning

confidence: 99%

Amyloidosis: What does pathology offer? The evolving field of tissue biopsy

Riefolo

Conti

Longhi

et al. 2022

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

show abstract

“…By exploring a wide range of in silico experimental conditions, these models return coherent predictions that can be useful for studying PD. Further investigation in this direction should focus on whether and how these results apply to in vivo settings to provide insights into the mechanisms of neurodegeneration and, possibly, inform therapeutic strategy design [58].…”

Section: Nucleation-conversion-polymerization Modelsmentioning

confidence: 99%

“…To this end, both groups of models would benefit from calibration and validation against measurements of aggregate levels in living systems. However, the availability of this quantitative information is limited by technical difficulties in monitoring the time evolution of aggregates and addressing the heterogeneous and elusive nature of oligomers [58]. As a result, chemical kinetic models have been trained mainly on in vitro data.…”

Section: In Vitro/in Vivo Translationmentioning

confidence: 99%

“…On the other hand, concentrations used in vitro are comparable to those estimated in vivo at presynaptic terminals [102-105]. Such a potential discrepancy in αsyn concentrations may hamper translatability due to the strong dependence of aggregation rates on initial protein levels [58,106]. Nevertheless, studying aggregation mechanisms in silico can bridge in vitro and in vivo settings.…”

Section: In Vitro/in Vivo Translationmentioning

confidence: 99%

See 1 more Smart Citation

Mechanistic models of α-synuclein homeostasis for Parkinson's disease: A blueprint for therapeutic intervention

Righetti

Antonello

Marchetti

et al. 2022

Front. Appl. Math. Stat.

View full text Add to dashboard Cite

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide, yet there is no disease-modifying therapy up to this date. The biological complexity underlying PD hampers the investigation of the principal contributors to its pathogenesis. In this context, mechanistic models grounded in molecular-level knowledge provide virtual labs to uncover the primary events triggering PD onset and progression and suggest promising therapeutic targets. Multiple modeling efforts in PD research have focused on the pathological role of α-synuclein (αsyn), a presynaptic protein that emerges from the intricate molecular network as a crucial driver of neurodegeneration. Here, we collect the advances in mathematical modeling of αsyn homeostasis, focusing on aggregation and degradation pathways, and discussing potential modeling improvements and possible implications in PD therapeutic strategy design.

show abstract

“…At worst, exposed hydrophobic patches cause the misfolded protein to aggregate and trigger the misfolding of neighboring proteins, resulting in a highly toxic chain reaction of amyloid fiber formation. Indeed, several diseases including Parkinson's and Alzheimer's diseases involve a breakdown of proper protein folding and the buildup of amyloid fibers [ 1 ]. Survival therefore depends on molecular chaperones, a class of proteins that stabilize and promote the proper folding of other proteins.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic insights into protein folding by the eukaryotic chaperonin complex CCT

Smith

Willardson

2022

Biochemical Society Transactions

View full text Add to dashboard Cite

The cytosolic chaperonin CCT is indispensable to eukaryotic life, folding the cytoskeletal proteins actin and tubulin along with an estimated 10% of the remaining proteome. However, it also participates in human diseases such as cancer and viral infections, rendering it valuable as a potential therapeutic target. CCT consists of two stacked rings, each comprised of eight homologous but distinct subunits, that assists the folding of a remarkable substrate clientele that exhibits both broad diversity and specificity. Much of the work in recent years has been aimed at understanding the mechanisms of CCT substrate recognition and folding. These studies have revealed new binding sites and mechanisms by which CCT uses its distinctive subunit arrangement to fold structurally unrelated substrates. Here, we review recent structural insights into CCT-substrate interactions and place them into the broader context of CCT function and its implications for human health.

show abstract

Molecular mechanisms of amyloid formation in living systems

Abstract: Fibrillar protein aggregation is a hallmark of a variety of human diseases. Examples include the deposition of amyloid-β and tau in Alzheimer’s disease, and that of α-synuclein in Parkinson’s disease....

Cited by 39 publications

References 187 publications

Amyloidosis: What does pathology offer? The evolving field of tissue biopsy

Amyloidosis: What does pathology offer? The evolving field of tissue biopsy

Mechanistic models of α-synuclein homeostasis for Parkinson's disease: A blueprint for therapeutic intervention

Mechanistic insights into protein folding by the eukaryotic chaperonin complex CCT

Contact Info

Product

Resources

About