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Antisense oligonucleotides targeting alpha-synuclein reduce pre-formed fibril-induced Lewy pathology and improve some domains of cognitive and motor performance

Sydney Weber Boutros, Jacob Raber, Vivek K. Unni
doi: https://doi.org/10.1101/2020.10.21.349191
Sydney Weber Boutros
1Department of Behavioral Neuroscience, OHSU
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Jacob Raber
1Department of Behavioral Neuroscience, OHSU
2Department of Neurology, OHSU
3Departments of Psychiatry and Radiation Medicine, Division of Neuroscience, ONPRC, OHSU
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Vivek K. Unni
2Department of Neurology, OHSU
4Jungers Center for Neuroscience Research and OHSU Parkinson Center
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  • For correspondence: unni@ohsu.edu
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Abstract

Alpha-synuclein (αsyn) is a small protein involved in neurodegenerative diseases known as synucleinopathies. The phosphorylated form (psyn) is the primary component of protein aggregates known as Lewy bodies (LBs), which are the hallmark of diseases such as Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). Synucleinopathies might spread in a prion-like fashion, leading to a progressive emergence of symptoms over time. αsyn pre-formed fibrils (PFFs) induce LB-like pathology in wild-type (WT) mice, but there are remaining questions about the progressive “spreading” of pathology and the cognitive and behavioral effects. Here, we induced LB-like pathology in the bilateral motor cortex of WT mice and assessed behavioral and cognitive performance. As there are no long-term effective treatments for synucleinopathies, and no therapies slow or reduce the spreading of LBs, we also assessed the effects of a mouse αsyn-targeted antisense oligonucleotides (ASOs) on pathology and behavioral and cognitive performance starting 5 weeks after ASO treatment. At 3 months post-PFF injection (mpi), mice injected with PFFs showed cognitive impairments and mild motor impairments. At 6 mpi, PFF-injected mice showed further cognitive and motor impairments that were partially ameliorated by the ASO. ASO treatment also reduced LB-like pathology, and pathology was significantly correlated with cognitive measures. However, the particular mouse ASO used in these assays was also associated with some possible off-target effects, defined as effects not involving lowering of αsyn, such as a decline in body weight. These results add to what is known about the progressive nature of the PFF model of synucleinopathies. These data also support the therapeutic potential of ASOs to improve Lewy pathology and associated behavioral and cognitive phenotypes.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 21, 2020.
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Antisense oligonucleotides targeting alpha-synuclein reduce pre-formed fibril-induced Lewy pathology and improve some domains of cognitive and motor performance
Sydney Weber Boutros, Jacob Raber, Vivek K. Unni
bioRxiv 2020.10.21.349191; doi: https://doi.org/10.1101/2020.10.21.349191
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Antisense oligonucleotides targeting alpha-synuclein reduce pre-formed fibril-induced Lewy pathology and improve some domains of cognitive and motor performance
Sydney Weber Boutros, Jacob Raber, Vivek K. Unni
bioRxiv 2020.10.21.349191; doi: https://doi.org/10.1101/2020.10.21.349191

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