In Silico, in Vitro, and in Vivo Evaluation of New Candidates for α-Synuclein PET Imaging

Verdurand, Mathieu; Levigoureux, Elise; Zeinyeh, Waël; Berthier, Laurent; Mendjel-Herda, Meriem; Cadarossanesaib, Florence; Bouillot, Caroline; Iecker, Thibault; Terreux, Raphaël; Lancelot, Sophie; Chauveau, Fabien; Billard, Thierry; Zimmer, Luc

doi:10.1021/acs.molpharmaceut.8b00229

Cited by 42 publications

(73 citation statements)

References 50 publications

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“…This could be achieved by detection of CSF aSyn with enzyme-linked sandwich-type immunosorbent assays (ELISA) or even more precise analyzes for its aggregated states with Protein Misfolding Cyclic Amplification (PMCA) or Real-Time Quaking-Induced Conversion (RT-QuIC) [128]. A non-invasive in vivo analysis of the brain aSyn load would be possible via nuclear medicine PET or SPECT methodology, but this is currently not established [129].…”

Section: Discussionmentioning

confidence: 99%

Novel Immunotherapeutic Approaches to Target Alpha-Synuclein and Related Neuroinflammation in Parkinson’s Disease

Zella

Metzdorf

Ostendorf

et al. 2019

Cells

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The etiology of Parkinson’s disease (PD) is significantly influenced by disease-causing changes in the protein alpha-Synuclein (aSyn). It can trigger and promote intracellular stress and thereby impair the function of dopaminergic neurons. However, these damage mechanisms do not only extend to neuronal cells, but also affect most glial cell populations, such as astroglia and microglia, but also T lymphocytes, which can no longer maintain the homeostatic CNS milieu because they produce neuroinflammatory responses to aSyn pathology. Through precise neuropathological examination, molecular characterization of biomaterials, and the use of PET technology, it has been clearly demonstrated that neuroinflammation is involved in human PD. In this review, we provide an in-depth overview of the pathomechanisms that aSyn elicits in models of disease and focus on the affected glial cell and lymphocyte populations and their interaction with pathogenic aSyn species. The interplay between aSyn and glial cells is analyzed both in the basic research setting and in the context of human neuropathology. Ultimately, a strong rationale builds up to therapeutically reduce the burden of pathological aSyn in the CNS. The current antibody-based approaches to lower the amount of aSyn and thereby alleviate neuroinflammatory responses is finally discussed as novel therapeutic strategies for PD.

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Section: Discussionmentioning

confidence: 99%

Novel Immunotherapeutic Approaches to Target Alpha-Synuclein and Related Neuroinflammation in Parkinson’s Disease

Zella

Metzdorf

Ostendorf

et al. 2019

Cells

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“…We will also need to develop PET‐tracers that can detect aSyn, to enable longitudinal studies in patients, and even in individuals at risk (based on genetic factors, for example). Attempts to develop radioligands able to bind to different forms of aSyn are ongoing, but we still face major challenges such as selectivity, or blood–brain barrier penetration (Cairns et al, ; Merchant et al, ; Verdurand et al, ). However, the coming years may bring novel developments in this area.…”

Section: Pd Biomarkers Based On Asynmentioning

confidence: 99%

Synucleinopathies: Where we are and where we need to go

Brás

Dominguez-Meijide

Gerhardt

et al. 2020

Journal of Neurochemistry

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All authors contributed equally to this manuscript. This artic le is relat ed to the Speci al Issue "Synuc lein" Abbreviations: A30P, aSyn substitution of an alanine for a proline at position 30; A53E, aSyn substitution of an alanine for a glutamic acid at position 53; A53T, aSyn substitution of an alanine for a tyrosine at position 53; ALP, autophagy-lysosomal pathway; APLP1, Aβ precursor-like protein 1; aSyn, alpha-synuclein; BiFC, bimolecular fluorescence complementation; CMA, Chaperone-mediated autophagy; CNS, central nervous system; co-IP, co-immunoprecipitation; Cryo-EM, cryo-electron microscopy; CSF, cerebrospinal fluid; Cu, copper; DLB, dementia with Lewy bodies; E46K, aSyn substitution of a glutamic acid for a lysine at position 46; ENS, enteric nervous system; ER, endoplasmic reticulum; Fe, iron; FRET, fluorescence resonance energy transfer; G51D, aSyn substitution of a glycine for a aspartic acid at position 51Abstract Synucleinopathies are a group of disorders characterized by the accumulation of inclusions rich in the a-synuclein (aSyn) protein. This group of disorders includes Parkinson's disease, dementia with Lewy bodies (DLB), multiple systems atrophy, and pure autonomic failure (PAF). In addition, genetic alterations (point mutations and multiplications) in the gene encoding for aSyn (SNCA) are associated with familial forms of Parkinson's disease, the most common synucleinopathy. The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of Synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein meeting took place in Ofir, a city in the outskirts of Porto, Portugal. The meeting, entitled "Synuclein Meeting 2019:Where we are and where we need to go", brought together >300 scientists studying both clinical and molecular aspects of synucleinopathies. The meeting covered a many of the open questions in the field, in a format that prompted open discussions between the participants, and underscored the need for additional research that, hopefully, will lead to future therapies for a group of as of yet incurable disorders. Here, we provide a summary of the topics discussed in each session and highlight what we know, what we do not know, and what progress needs to be made in order to enable the field to continue to advance. We are confident this systematic assessment of where we stand will be useful to steer the field and contribute to filling knowledge gaps that may form the foundations for future therapeutic strategies, which is where we need to go.

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“…Following the recent success with bringing amyloid and tau PET tracers into humans, the desire for radioligands targeting other misfolded proteins like α-synuclein or TDP-43 is evident. However, developing PET radiotracers that target misfolded proteins beyond Aβ is challenging as these proteins (i) are mainly intracellularly localized, (ii) appear in a much lower concentration than Aβ plaques (Villemagne et al 2015; Lois et al 2018; Harada et al 2018; Verdurand et al 2018), and (iii) have β-sheet binding motives which are rather similar to those of amyloid aggregates. Despite intensive efforts to develop α-synuclein- and TDP-43-targeting PET radiotracers, until now no suitable substance has been described (Mathis et al 2017).…”

Section: Role Of Pet Imaging In Neurodegenerative Diseasesmentioning

confidence: 99%

Current radiotracers to image neurodegenerative diseases

Tiepolt

Patt

Aghakhanyan

et al. 2019

EJNMMI radiopharm. chem.

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The term of neurodegenerative diseases covers a heterogeneous group of disorders that are distinguished by progressive degeneration of the structure and function of the nervous system such as dementias, movement disorders, motor neuron disorders, as well as some prion disorders. In recent years, a paradigm shift started for the diagnosis of neurodegenerative diseases, for which successively clinical testing is supplemented by biomarker information. In research scenarios, it was even proposed recently to substitute the current syndromic by a biological definition of Alzheimer’s diseases. PET examinations with various radiotracers play an important role in providing non-invasive biomarkers and co-morbidity information in neurodegeneration. Information on co-morbidity, e.g. Aβ plaques and Lewy-bodies or Aβ plaques in patients with aphasia or the absence of Aβ plaques in clinical AD patients are of interest to expand our knowledge about the pathogenesis of different phenotypically defined neurodegenerative diseases. Moreover, this information is also important in therapeutic trials targeting histopathological abnormalities. The aim of this review is to present an overview of the currently available radiotracers for imaging neurodegenerative diseases in research and in routine clinical settings. In this context, we also provide a short summary of the most frequent neurodegenerative diseases from a nuclear medicine point of view, their clinical and pathophysiological as well as nuclear imaging characteristics, and the resulting need for new radiotracers.

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In Silico, in Vitro, and in Vivo Evaluation of New Candidates for α-Synuclein PET Imaging

Cited by 42 publications

References 50 publications

Novel Immunotherapeutic Approaches to Target Alpha-Synuclein and Related Neuroinflammation in Parkinson’s Disease

Novel Immunotherapeutic Approaches to Target Alpha-Synuclein and Related Neuroinflammation in Parkinson’s Disease

Synucleinopathies: Where we are and where we need to go

Current radiotracers to image neurodegenerative diseases

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