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LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model.

Publication ,  Journal Article
Zhao, HT; John, N; Delic, V; Ikeda-Lee, K; Kim, A; Weihofen, A; Swayze, EE; Kordasiewicz, HB; West, AB; Volpicelli-Daley, LA
Published in: Mol Ther Nucleic Acids
September 15, 2017

No treatments exist to slow or halt Parkinson's disease (PD) progression; however, inhibition of leucine-rich repeat kinase 2 (LRRK2) activity represents one of the most promising therapeutic strategies. Genetic ablation and pharmacological LRRK2 inhibition have demonstrated promise in blocking α-synuclein (α-syn) pathology. However, LRRK2 kinase inhibitors may reduce LRRK2 activity in several tissues and induce systemic phenotypes in the kidney and lung that are undesirable. Here, we test whether antisense oligonucleotides (ASOs) provide an alternative therapeutic strategy, as they can be restricted to the CNS and provide a stable, long-lasting reduction of protein throughout the brain. Administration of LRRK2 ASOs to the brain reduces LRRK2 protein levels and fibril-induced α-syn inclusions. Mice exposed to α-syn fibrils treated with LRRK2 ASOs show more tyrosine hydroxylase (TH)-positive neurons compared to control mice. Furthermore, intracerebral injection of LRRK2 ASOs avoids unwanted phenotypes associated with loss of LRRK2 expression in the periphery. This study further demonstrates that a reduction of endogenous levels of normal LRRK2 reduces the formation of α-syn inclusions. Importantly, this study points toward LRRK2 ASOs as a potential therapeutic strategy for preventing PD-associated pathology and phenotypes without causing potential adverse side effects in peripheral tissues associated with LRRK2 inhibition.

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Published In

Mol Ther Nucleic Acids

DOI

ISSN

2162-2531

Publication Date

September 15, 2017

Volume

8

Start / End Page

508 / 519

Location

United States

Related Subject Headings

  • 3101 Biochemistry and cell biology
  • 1103 Clinical Sciences
  • 0601 Biochemistry and Cell Biology
 

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Zhao, H. T., John, N., Delic, V., Ikeda-Lee, K., Kim, A., Weihofen, A., … Volpicelli-Daley, L. A. (2017). LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model. Mol Ther Nucleic Acids, 8, 508–519. https://doi.org/10.1016/j.omtn.2017.08.002
Zhao, Hien Tran, Neena John, Vedad Delic, Karli Ikeda-Lee, Aneeza Kim, Andreas Weihofen, Eric E. Swayze, Holly B. Kordasiewicz, Andrew B. West, and Laura A. Volpicelli-Daley. “LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model.Mol Ther Nucleic Acids 8 (September 15, 2017): 508–19. https://doi.org/10.1016/j.omtn.2017.08.002.
Zhao HT, John N, Delic V, Ikeda-Lee K, Kim A, Weihofen A, et al. LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model. Mol Ther Nucleic Acids. 2017 Sep 15;8:508–19.
Zhao, Hien Tran, et al. “LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model.Mol Ther Nucleic Acids, vol. 8, Sept. 2017, pp. 508–19. Pubmed, doi:10.1016/j.omtn.2017.08.002.
Zhao HT, John N, Delic V, Ikeda-Lee K, Kim A, Weihofen A, Swayze EE, Kordasiewicz HB, West AB, Volpicelli-Daley LA. LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model. Mol Ther Nucleic Acids. 2017 Sep 15;8:508–519.
Journal cover image

Published In

Mol Ther Nucleic Acids

DOI

ISSN

2162-2531

Publication Date

September 15, 2017

Volume

8

Start / End Page

508 / 519

Location

United States

Related Subject Headings

  • 3101 Biochemistry and cell biology
  • 1103 Clinical Sciences
  • 0601 Biochemistry and Cell Biology