Peripheral alpha-synuclein levels in patients with genetic and non-genetic forms of Parkinson's disease

Emmanouilidou, Evangelia; Papagiannakis, Nikolaos; Kouloulia, Stella; Galaziou, Aikaterini; Antonellou, Roubina; Papadimitriou, Dimitra; Athanasiadou, Aglaia; Bozi, Maria; Koros, Christos; Maniati, Matina; Vekrellis, Kostas; Ioannou, Penelope C.; Stefanis, Leonidas

doi:10.1016/j.parkreldis.2020.03.014

Cited by 13 publications

(10 citation statements)

References 41 publications

(54 reference statements)

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“…Although small variations in plasma α‐synuclein levels were observed in GBA‐PD and NM‐PD compared with HC, no statistical differences emerged among groups, showing that this parameter is not distinctive for the GBA‐PD condition and confirming its unreliability as a surrogate marker of synucleinopathy 19,20 . Conversely, we found significantly higher exosome‐associated α‐synuclein in both PD groups compared with HC, in line with previous studies that specifically associated increased exosomal α‐synuclein with PD 12,21,22 .…”

Section: Discussionsupporting

confidence: 89%

Profiling the Biochemical Signature of GBA‐Related Parkinson's Disease in Peripheral Blood Mononuclear Cells

Avenali

Cerri²,

Ongari

et al. 2021

Movement Disorders

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Background GBA mutations are the commonest genetic risk factor for Parkinson's disease (PD) and also impact disease progression. Objective The objective of this study was to define a biochemical profile that could distinguish GBA‐PD from non‐mutated PD. Methods 29 GBA‐PD, 37 non‐mutated PD, and 40 controls were recruited; α‐synuclein levels in plasma, exosomes, and peripheral blood mononuclear cells were analyzed, GCase and main GCase‐related lysosomal proteins in peripheral blood mononuclear cells were measured. Results Assessment of plasma and exosomal α‐synuclein levels did not allow differentiation between GBA‐PD and non‐mutated PD; conversely, measurements in peripheral blood mononuclear cells clearly distinguished GBA‐PD from non‐mutated PD, with the former group showing significantly higher α‐synuclein levels, lower GCase activity, higher LIMP‐2, and lower Saposin C levels. Conclusion We propose peripheral blood mononuclear cells as an easily accessible and manageable model to provide a distinctive biochemical profile of GBA‐PD, potentially useful for patient stratification or selection in clinical trials. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

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Section: Discussionsupporting

confidence: 89%

Profiling the Biochemical Signature of GBA‐Related Parkinson's Disease in Peripheral Blood Mononuclear Cells

Avenali

Cerri²,

Ongari

et al. 2021

Movement Disorders

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“…Since exosomes are considered as potential carriers of toxic proteins, their role in PD pathogenesis has been extensively studied via the measurement of their levels in patient-derived biological fluids. Specifically, it has been demonstrated that although the levels of αSyn in the CSF of PD patients were lower compared to controls, the exosome-associated αSyn in the plasma of these patients was significantly higher [ 115 , 116 , 117 , 118 ]. As mentioned above, PD pathogenesis is closely linked to lysosomal function, with up to 7% of patients carrying a loss-of-function mutation in the GBA1 gene that encodes for the lysosomal enzyme β-glucocerebrosidase (GCase) [ 119 , 120 , 121 ].…”

Section: A Key Role Of Exosomes In Alpha-synucleinopathiesmentioning

confidence: 99%

Exosomes in Alpha-Synucleinopathies: Propagators of Pathology or Potential Candidates for Nanotherapeutics?

et al. 2022

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The pathological accumulation of alpha-synuclein governs the pathogenesis of neurodegenerative disorders, such as Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, collectively termed alpha-synucleinopathies. Alpha-synuclein can be released in the extracellular space, partly via exosomes, and this extracellular protein pool may contribute to disease progression by facilitating the spread of pathological alpha-synuclein or activating immune cells. The content of exosomes depends on their origin and includes specific proteins, lipids, functional mRNAs and various non-coding RNAs. Given their ability to mediate intercellular communication via the transport of multilevel information, exosomes are considered to be transporters of toxic agents. Beyond neurons, glial cells also release exosomes, which may contain inflammatory molecules and this glia-to-neuron or neuron-to-glia transmission of exosomal alpha-synuclein may contribute to the propagation of pathology and neuroinflammation throughout the brain. In addition, as their content varies as per their originating and recipient cells, these vesicles can be utilized as a diagnostic biomarker for early disease detection, whereas targeted exosomes may be used as scaffolds to deliver therapeutic agents into the brain. This review summarizes the current knowledge regarding the role of exosomes in the progression of alpha-synuclein-related pathology and their potential use as biomarkers and nanotherapeutics in alpha-synucleinopathies.

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“…A number of studies have sought uid biomarkers for synucleinopathies) [197][198][199][200][201][202], but reliable biomarkers are not yet widely available. Recently, biomarkers directly assessing α-synuclein have been developed using RT-QuIC or PMCA.…”

Section: α-Synuclein Strains As Potential Biomarkersmentioning

confidence: 99%

Neuropathology, Genetics and Biomarkers of Synucleinopathies

Koga

Sekiya

Kondru

et al. 2021

Preprint

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Synucleinopathies are clinically and pathologically heterogeneous disorders characterized by pathologic aggregates of α-synuclein in neurons and glia, in the form of Lewy bodies, Lewy neurites, neuronal cytoplasmic inclusions, and glial cytoplasmic inclusions (GCIs). Synucleinopathies can be divided into two major disease entities: Lewy body disease (LBD) and multiple system atrophy (MSA). Common clinical presentations of LBD are Parkinson's disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB), while MSA has two major clinical subtypes, MSA with predominant cerebellar ataxia (MSA-C) and MSA with predominant parkinsonism (MSA-P). There are currently no disease-modifying therapies for the synucleinopathies, but elucidation of genetics and mechanisms of α-synuclein conversion to pathologic oligomers and insoluble fibrils offer hope for eventual therapies. It remains unclear how α-synuclein can be associated with distinct cellular pathologies (e.g., Lewy bodies and GCI) and what factors determine neuroanatomical and cell type vulnerability. Accumulating evidence from in vitro and in vivo experiments suggests that α-synuclein species derived from LBD and MSA are distinct "strains" having different seeding properties. Recent advancements in in vitro seeding assays, such as real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), not only demonstrate distinct seeding activity in the synucleinopathies, but also offer exciting opportunities for molecular diagnosis using readily accessible peripheral tissues. Cryogenic electron microscopy (cryo-EM) structural studies of α-synuclein derived from recombinant or brain-derived filaments provide new insight into mechanisms of seeding in synucleinopathies. In this review, we describe clinical, genetic and neuropathologic features of synucleinopathies, including a review of classification and staging schemes for LBD. We also review evidence supporting the existence of distinct α-synuclein strains in LBD and MSA.

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Peripheral alpha-synuclein levels in patients with genetic and non-genetic forms of Parkinson's disease

Cited by 13 publications

References 41 publications

Profiling the Biochemical Signature of GBA‐Related Parkinson's Disease in Peripheral Blood Mononuclear Cells

Profiling the Biochemical Signature of GBA‐Related Parkinson's Disease in Peripheral Blood Mononuclear Cells

Exosomes in Alpha-Synucleinopathies: Propagators of Pathology or Potential Candidates for Nanotherapeutics?

Neuropathology, Genetics and Biomarkers of Synucleinopathies

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