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Open Access 01-12-2024 | Pathology | Research

Effects of local reduction of endogenous α-synuclein using antisense oligonucleotides on the fibril-induced propagation of pathology through the neural network in wild-type mice

Authors: Tatsuhiko Sano, Tetsuya Nagata, Satoe Ebihara, Kie Yoshida-Tanaka, Ayako Nakamura, Asuka Sasaki, Aki Shimozawa, Hideki Mochizuki, Toshiki Uchihara, Masato Hasegawa, Takanori Yokota

Published in: Acta Neuropathologica Communications | Issue 1/2024

Abstract

In Parkinson's disease and other synucleinopathies, fibrillar forms of α-synuclein (aSyn) are hypothesized to structurally convert and pathologize endogenous aSyn, which then propagates through the neural connections, forming Lewy pathologies and ultimately causing neurodegeneration. Inoculation of mouse-derived aSyn preformed fibrils (PFFs) into the unilateral striatum of wild-type mice causes widespread aSyn pathologies in the brain through the neural network. Here, we used the local injection of antisense oligonucleotides (ASOs) against Snca mRNA to confine the area of endogenous aSyn protein reduction and not to affect the PFFs properties in this model. We then varied the timing and location of ASOs injection to examine their impact on the initiation and propagation of aSyn pathologies in the whole brain and the therapeutic effect using abnormally-phosphorylated aSyn (pSyn) as an indicator. By injecting ASOs before or 0–14 days after the PFFs were inoculated into the same site in the left striatum, the reduction in endogenous aSyn in the striatum leads to the prevention and inhibition of the regional spread of pSyn pathologies to the whole brain including the contralateral right hemisphere. ASO post-injection inhibited extension from neuritic pathologies to somatic ones. Moreover, injection of ASOs into the right striatum prevented the remote regional spread of pSyn pathologies from the left striatum where PFFs were inoculated and no ASO treatment was conducted. This indicated that the reduction in endogenous aSyn protein levels at the propagation destination site can attenuate pSyn pathologies, even if those at the propagation initiation site are not inhibited, which is consistent with the original concept of prion-like propagation that endogenous aSyn is indispensable for this regional spread. Our results demonstrate the importance of recruiting endogenous aSyn in this neural network propagation model and indicate a possible potential for ASO treatment in synucleinopathies.

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Title: Effects of local reduction of endogenous α-synuclein using antisense oligonucleotides on the fibril-induced propagation of pathology through the neural network in wild-type mice
Authors: Tatsuhiko Sano
Tetsuya Nagata
Satoe Ebihara
Kie Yoshida-Tanaka
Ayako Nakamura
Asuka Sasaki
Aki Shimozawa
Hideki Mochizuki
Toshiki Uchihara
Masato Hasegawa
Takanori Yokota
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Pathology
Parkinson's Disease
Published in: Acta Neuropathologica Communications / Issue 1/2024
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-024-01766-3

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Effects of local reduction of endogenous α-synuclein using antisense oligonucleotides on the fibril-induced propagation of pathology through the neural network in wild-type mice

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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