Proteopathic Seed Amplification Assays for Neurodegenerative Disorders

Ferreira, Natália do Carmo; Caughey, Byron

doi:10.1016/j.cll.2020.04.002

Cited by 26 publications

(15 citation statements)

References 89 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For clinical applications, a reliable biomarker for the time point when interference with Aβ deposition will yield maximal clinical benefit, presumably before half-maximal Aβ deposition is reached, would be of utmost importance. Biomarkers for this early phase of Aβ deposition may include novel Aβ imaging computational approaches 10 , further improvement of ultrasensitive blood Aβ (or pTau) immunoassays 55 , or fluid assays to assess brain Aβ seeding activity 56 .…”

Section: Discussionmentioning

confidence: 99%

Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae

et al. 2022

View full text Add to dashboard Cite

Brain Aβ deposition is a key early event in the pathogenesis of Alzheimer´s disease (AD), but the long presymptomatic phase and poor correlation between Aβ deposition and clinical symptoms remain puzzling. To elucidate the dependency of downstream pathologies on Aβ, we analyzed the trajectories of cerebral Aβ accumulation, Aβ seeding activity, and neurofilament light chain (NfL) in the CSF (a biomarker of neurodegeneration) in Aβ-precursor protein transgenic mice. We find that Aβ deposition increases linearly until it reaches an apparent plateau at a late age, while Aβ seeding activity increases more rapidly and reaches a plateau earlier, coinciding with the onset of a robust increase of CSF NfL. Short-term inhibition of Aβ generation in amyloid-laden mice reduced Aβ deposition and associated glial changes, but failed to reduce Aβ seeding activity, and CSF NfL continued to increase although at a slower pace. When short-term or long-term inhibition of Aβ generation was started at pre-amyloid stages, CSF NfL did not increase despite some Aβ deposition, microglial activation, and robust brain Aβ seeding activity. A dissociation of Aβ load and CSF NfL trajectories was also found in familial AD, consistent with the view that Aβ aggregation is not kinetically coupled to neurotoxicity. Rather, neurodegeneration starts when Aβ seeding activity is saturated and before Aβ deposition reaches critical (half-maximal) levels, a phenomenon reminiscent of the two pathogenic phases in prion disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae

et al. 2022

View full text Add to dashboard Cite

show abstract

“…At the same time, the understanding of the "prion-like" behaviour of α-syn provided new perspectives for the development of novel diagnostic assays. Indeed, two seed amplification assays (SAAs) [17], namely protein misfolding cyclic amplification (PMCA) [18] and real-time quaking-induced conversion (RT-QuIC) [19], have been successfully applied for the detection of misfolded prion protein (PrPSc) in tissues and biological fluids of animals [20][21][22] and humans [23]. PMCA and RT-QuIC currently represent the best option to perform the diagnosis of prion diseases, such as Creutzfeldt-Jacob disease, in CSF [23] and other peripheral fluids and tissues [24,25].…”

Section: Introductionmentioning

confidence: 99%

Seed amplification assays for diagnosing synucleinopathies: the issue of influencing factors

Bellomo

Paciotti

Gatticchi

et al. 2021

Front. Biosci. (Landmark Ed)

View full text Add to dashboard Cite

Background: The prion-like misfolding and aggregation of α-synuclein (α-syn) is involved in the pathophysiology of Parkinson’s disease and other synucleinopathies. Seed amplification assays (SAAs) are biophysical tools that take advantage on the peculiar properties of prion proteins by amplifying small amounts of aggregates in biological fluids at the expense of recombinant monomeric protein added in solution. SAAs have emerged as the most promising tools for the diagnosis of synucleinopathies in vivo. However, the diagnostic outcome of SAAs depends on the aggregation kinetics of α-syn, which in turn is influenced by several experimental variables. Methods: In our work, we analysed the impact on SAAs of some of the most critical experimental factors by considering models that describe the aggregation kinetics of α-syn. Results: We started our analysis by making simulations to understand which kinetic models could explain the aggregation kinetics of α-syn during incubation/shaking cycles. Subsequently, under shaking/incubation cycles similar to the ones commonly used in SAAs, we tested the influence of some analytical variables such as monomer concentration, presence/absence of glass beads, pH, addition of human cerebrospinal fluid, and use of detergents on α-syn aggregation. Conclusions: Our investigation highlighted how optimization and standardization of experimental procedures for α-syn SAAs is of utmost relevance for the ultimate goal of applying these assays in clinical routine. Although these aspects have been evaluated with specific SAA protocols, most of the experimental variables considered influenced very general aggregation mechanisms of α-syn, thus making most of the results obtained from our analyses extendable to other protocols.

show abstract

“…31 Seeding assays, initially developed for prion diseases, are now being vigorously applied to a variety of tissues and fluids in synucleinopathies. 32 Capitalizing on the existence of strains of aSyn, these assays provide great promise for the development of disease specific biomarkers, and have recently been reported to distinguish PD and MSA in cerebrospinal fluid (CSF) with >95% sensitivity 33 as well as detecting abnormal aSyn in isolated RBD 34 and pure autonomic failure. 35 As these methods can be applied in a very short time frame using existing biosamples we now anticipate rapid development in this field.…”

Section: Copathologiesmentioning

confidence: 99%

The Discovery of α‐Synuclein in Lewy Pathology of Parkinson's Disease: The Inspiration of a Revolution

Visanji

Kovács

Lang

2021

Movement Disord Clin Pract

View full text Add to dashboard Cite

When tasked with selecting one of the most influential papers in the field since the 1950s, Spillantini et al 1 describing the presence of α-synuclein (aSyn) in Lewy bodies (LBs) in Parkinson's disease (PD) was our clear first choice. Following James Parkinson's description of the Shaking Palsy in 1817, progress in understanding PD mirrored the slowness of movement that characterizes the disease itself. Almost 100 years later, in 1912, Friedrich Lewy described the inclusion bodies we now recognize as the pathological hallmark of PD and a further 85 years later, investigation of the Contursi kindred, manifesting autosomal dominant PD, identified a causative single base mutation in SNCA. 2 It took just 2 months for Spillantini and colleagues to publish their landmark paper describing the presence of aSyn in LBs in idiopathic PD and dementia with Lewy bodies (DLB). In the 24 years since this short paper was published (Spillantini et al's article was less than half the length of this Viewpoint), it has catalyzed numerous advances in understanding the pathophysiology of synucleinopathies, amassing over 2,225 citations and influencing almost every aspect of research in PD and other neurodegenerative disorders.

show abstract

Proteopathic Seed Amplification Assays for Neurodegenerative Disorders

Cited by 26 publications

References 89 publications

Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae

Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae

Seed amplification assays for diagnosing synucleinopathies: the issue of influencing factors

The Discovery of α‐Synuclein in Lewy Pathology of Parkinson's Disease: The Inspiration of a Revolution

Contact Info

Product

Resources

About