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  Depopulation of dense α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson's disease model.

Wegrzynowicz, M., Bar-On, D., Calo’, L., Anichtchik, O., Iovino, M., Xia, J., et al. (2019). Depopulation of dense α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson's disease model. Acta Neuropathologica, (in press). doi:10.1007/s00401-019-02023-x.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-CB6E-E Version Permalink: http://hdl.handle.net/21.11116/0000-0003-CB72-8
Genre: Journal Article

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Wegrzynowicz, M., Author
Bar-On, D., Author
Calo’, L., Author
Anichtchik, O., Author
Iovino, M., Author
Xia, J., Author
Ryazanov, S.1, Author              
Leonov, A.1, Author              
Giese, A., Author
Dalley, J. W., Author
Griesinger, C.1, Author              
Ashery, U., Author
Spillantini, M. G., Author
Affiliations:
1Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society, ou_578567              

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Free keywords: Alpha-synuclein; Anle138b; Mouse model; Parkinson’s disease; Striatum; Substantia nigra; dSTORM
 Abstract: Parkinson's disease (PD) is characterized by the presence of α-synuclein aggregates known as Lewy bodies and Lewy neurites, whose formation is linked to disease development. The causal relation between α-synuclein aggregates and PD is not well understood. We generated a new transgenic mouse line (MI2) expressing human, aggregation-prone truncated 1-120 α-synuclein under the control of the tyrosine hydroxylase promoter. MI2 mice exhibit progressive aggregation of α-synuclein in dopaminergic neurons of the substantia nigra pars compacta and their striatal terminals. This is associated with a progressive reduction of striatal dopamine release, reduced striatal innervation and significant nigral dopaminergic nerve cell death starting from 6 and 12 months of age, respectively. In the MI2 mice, alterations in gait impairment can be detected by the DigiGait test from 9 months of age, while gross motor deficit was detected by rotarod test at 20 months of age when 50% of dopaminergic neurons in the substantia nigra pars compacta are lost. These changes were associated with an increase in the number and density of 20-500 nm α-synuclein species as shown by dSTORM. Treatment with the oligomer modulator anle138b, from 9 to 12 months of age, restored striatal dopamine release, prevented dopaminergic cell death and gait impairment. These effects were associated with a reduction of the inner density of large α-synuclein aggregates and an increase in dispersed small α-synuclein species as revealed by dSTORM. The MI2 mouse model recapitulates the progressive dopaminergic deficit observed in PD, showing that early synaptic dysfunction is associated to fine behavioral motor alterations, precedes dopaminergic axonal loss and neuronal death that become associated with a more consistent motor deficit upon reaching a certain threshold. Our data also provide new mechanistic insight for the effect of anle138b's function in vivo supporting that targeting α-synuclein aggregation is a promising therapeutic approach for PD.

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Language(s): eng - English
 Dates: 2019-05-31
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1007/s00401-019-02023-x
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Title: Acta Neuropathologica
Source Genre: Journal
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Pages: - Volume / Issue: - Sequence Number: (in press) Start / End Page: - Identifier: -