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

ABSTRACT: 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 ?-synuclein (?-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 ?-syn inclusions. Mice exposed to ?-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 ?-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.

SUBMITTER: Zhao HT

PROVIDER: S-EPMC5573879 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Zhao Hien Tran HT John Neena N Delic Vedad V Ikeda-Lee Karli K Kim Aneeza A Weihofen Andreas A Swayze Eric E EE Kordasiewicz Holly B HB West Andrew B AB Volpicelli-Daley Laura A LA

Molecular therapy. Nucleic acids 20170810

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 wheth ...[more]

PMID: 28918051

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Project description:Leucine-rich repeat kinase 2 (LRRK2) and α-synuclein share enigmatic roles in the pathobiology of Parkinson's disease (PD). LRRK2 mutations are a common genetic cause of PD which, in addition to neurodegeneration, often present with abnormal deposits of α-synuclein in the form of Lewy-related pathology. As Lewy-related pathology is a prominent neuropathologic finding in sporadic PD, the relationship between LRRK2 and α-synuclein has garnered considerable interest. However, whether and how LRRK2 might influence the accumulation of Lewy-related pathology remains poorly understood. Through stereotactic injection of mouse α-synuclein pre-formed fibrils (PFF), we modeled the spread of Lewy-related pathology within forebrain regions where LRRK2 is most highly expressed. The impact of LRRK2 genotype on the formation of α-synuclein inclusions was evaluated at 1-month post-injection. Neither deletion of LRRK2 nor G2019S LRRK2 knockin appreciably altered the burden of α- synuclein pathology at this early timepoint. These observations fail to provide support for a robust pathophysiologic interaction between LRRK2 and α-synuclein in the forebrain in vivo . There was, however, a modest reduction in microglial activation induced by PFF delivery in the hippocampus of LRRK2 knockout mice, suggesting that LRRK2 may contribute to α-synuclein-induced neuroinflammation. Collectively, our data indicate that the pathological accumulation of α-synuclein in the mouse forebrain is largely independent of LRRK2.HighlightsAdult mice accumulate α-synuclein pathology in the hippocampus and cortex following stereotactic injection with α-synuclein PFFs, with negligible influence of LRRK2 genotype. Hippocampal and cortical α-synuclein pathology elicits the concomitant accrual of phosphorylated tau, reactive astrogliosis, and microglial activation. Absence of endogenous LRRK2 attenuates microglial activation in the dorsal hippocampus induced by PFFs, but not in the entorhinal cortex. Accumulation of α-synuclein inclusions and related neuropathologic changes were strongly associated across the hippocampal dorsal-ventral axis, regardless of LRRK2 genotype.

Dataset Information

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

Publications

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

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