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      Targeting α-synuclein by PD03 AFFITOPE® and Anle138b rescues neurodegenerative pathology in a model of multiple system atrophy: clinical relevance

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          Abstract

          Background

          Misfolded oligomeric α-synuclein plays a pivotal role in the pathogenesis of α-synucleinopathies including Parkinson’s disease and multiple system atrophy, and its detection parallels activation of microglia and a loss of neurons in the substantia nigra pars compacta. Here we aimed to analyze the therapeutic efficacy of PD03, a new AFFITOPE® immunotherapy approach, either alone or in combination with Anle138b, in a PLP-α-syn mouse model.

          Methods

          The PLP-α-syn mice were treated with PD03 immunotherapy, Anle138b, or a combination of two. Five months after study initiation, the mice underwent behavioral testing and were sacrificed for neuropathological analysis. The treatment groups were compared to the vehicle group with regard to motor performance, nigral neuronal loss, microglial activation and α-synuclein pathology.

          Results

          The PLP-α-syn mice receiving the PD03 or Anle138b single therapy showed improvement of gait deficits and preservation of nigral dopaminergic neurons associated with the reduced α-synuclein oligomer levels and decreased microglial activation. The combined therapy with Anle138b and PD03 resulted in lower IgG binding in the brain as compared to the single immunotherapy with PD03.

          Conclusions

          PD03 and Anle138b can selectively target oligomeric α-synuclein, resulting in attenuation of neurodegeneration in the PLP-α-syn mice. Both approaches are potential therapies that should be developed further for disease modification in α-synucleinopathies.

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          Most cited references25

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          Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome).

          Glial cytoplasmic inclusions (GCIs) were demonstrated by silver staining, immunocytochemistry and by electron microscopy in the central nervous system (CNS) of 11 patients with various combinations of striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome. Although their configuration in light microscope can sometimes resemble neurofibrillary tangles, their cellular localisation, measurements, ultrastructure, immunocytochemical characteristics and regional distribution all differ from these Alzheimer type changes. The majority of GCIs were localized in the white matter and appeared to be accompanied by an increase in the number of interfascicular oligodendroglial cells and pallor or loss of myelin staining. Our histological, ultrastructural and immunocytochemical findings all indicate that the cells which contain GCIs are oligodendrocytes and the inclusions themselves are composed of tubular structures. The presence of the until now unknown GCIs in all the 11 CNS, but not in age- and sex-matched control brains, indicates that GCI is a cellular change characteristic of multiple system atrophy and the three syndromes are various manifestations of the same disease.
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            Effects of alpha-synuclein immunization in a mouse model of Parkinson's disease.

            Abnormal folding of alpha-synuclein (alpha-syn) is thought to lead to neurodegeneration and the characteristic symptoms of Lewy body disease (LBD). Since previous studies suggest that immunization might be a potential therapy for Alzheimer's disease, we hypothesized that immunization with human (h)alpha-syn might have therapeutic effects in LBD. For this purpose, halpha-syn transgenic (tg) mice were vaccinated with halpha-syn. In mice that produced high relative affinity antibodies, there was decreased accumulation of aggregated halpha-syn in neuronal cell bodies and synapses that was associated with reduced neurodegeneration. Furthermore, antibodies produced by immunized mice recognized abnormal halpha-syn associated with the neuronal membrane and promoted the degradation of halpha-syn aggregates, probably via lysosomal pathways. Similar effects were observed with an exogenously applied FITC-tagged halpha-syn antibody. These results suggest that vaccination is effective in reducing neuronal accumulation of halpha-syn aggregates and that further development of this approach might have a potential role in the treatment of LBD.
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              Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies.

              Alpha-synuclein forms the major component of Lewy bodies and Lewy neurites, the defining neuropathological characteristics of Parkinson's disease and dementia with Lewy bodies. Here we show that alpha-synuclein is also the major component of the filamentous inclusions of multiple system atrophy which comprises several neurodegenerative diseases with a shared filamentous pathology in nerve cells and glial cells. These findings provide an unexpected link between multiple system atrophy and Lewy body disorders and establish that alpha-synucleinopathies constitute a major class of human neurodegenerative disorder.
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                Author and article information

                Contributors
                nadia.stefanova@i-med.ac.at
                Journal
                Transl Neurodegener
                Transl Neurodegener
                Translational Neurodegeneration
                BioMed Central (London )
                2047-9158
                24 September 2020
                24 September 2020
                2020
                : 9
                : 38
                Affiliations
                [1 ]GRID grid.5361.1, ISNI 0000 0000 8853 2677, Division of Neurobiology, Department of Neurology, , Innsbruck Medical University, ; 6020 Innsbruck, Austria
                [2 ]GRID grid.452292.a, ISNI 0000 0004 0404 6321, AFFIRIS AG, ; Vienna, Austria
                [3 ]GRID grid.5252.0, ISNI 0000 0004 1936 973X, Center for Neuropathology and Prion Research, , Ludwig-Maximilians-University, ; Munich, Germany
                [4 ]GRID grid.418140.8, ISNI 0000 0001 2104 4211, Max Planck Institute for Biophysical Chemistry, ; Göttingen, Germany
                [5 ]Present Address: Origenis GmbH, Munich, Germany
                Author information
                http://orcid.org/0000-0001-8188-639X
                Article
                217
                10.1186/s40035-020-00217-y
                7513530
                32972456
                995c687a-8b31-4b94-afe4-db53ef48c38f
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 24 March 2020
                : 8 September 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100002428, Austrian Science Fund;
                Award ID: W1206-08
                Award ID: I2102
                Award ID: F4414
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100011272, FP7 Health;
                Award ID: 603646
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                Neurosciences
                α-synuclein,immunotherapy,oligomer modulation,target engagement,substantia nigra,microglia

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