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Splice-Switching Antisense Oligonucleotides Reduce LRRK2 Kinase Activity in Human LRRK2 Transgenic Mice
Joanna A Korecka1, Ria Thomas1, Anthony J Hinrich2
1Neuroregeneration Research Institute, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA.
Abstract:
Parkinson's disease (PD) is a progressive neurological disorder estimated to affect 7-10 million people worldwide. There is no treatment available that cures or slows the progression of PD. Elevated leucine-rich repeat kinase 2 (LRRK2) activity has been associated with genetic and sporadic forms of PD and, thus, reducing LRRK2 function is a promising therapeutic strategy. We have previously reported that an antisense oligonucleotide (ASO) that blocks splicing of LRRK2 exon 41, which encodes part of the kinase domain, reverses aberrant endoplasmic reticulum (ER) calcium levels and mitophagy defects in PD patient-derived cell lines harboring the LRRK2 G2019S mutation. In this study, we show that treating transgenic mice expressing human wild-type or G2019S LRRK2 with a single intracerebroventricular injection of ASO induces exon 41 skipping and results in a decrease in phosphorylation of the LRRK2 kinase substrate RAB10. Exon 41 skipping also reverses LRRK2 kinase-dependent changes in LC3B II/I ratios, a marker for the autophagic process. These results demonstrate the potential of LRRK2 exon 41 skipping as a possible therapeutic strategy to modulate pathogenic LRRK2 kinase activity associated with PD development.
Insights
An antisense oligonucleotide (ASO) targeting leucine-rich repeat kinase 2 (LRRK2) exon 41 effectively reduces its activity in mouse models. This exon skipping shows promise for treating Parkinson's disease by modulating pathogenic LRRK2 kinase activity.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting millions globally, with no current cure or disease-modifying treatments.
- Elevated leucine-rich repeat kinase 2 (LRRK2) kinase activity is implicated in both genetic and sporadic forms of PD, making it a key therapeutic target.
- Previous research demonstrated that blocking LRRK2 exon 41 splicing with an antisense oligonucleotide (ASO) corrects cellular defects in PD patient-derived cell lines.
Purpose of the Study:
- To investigate the therapeutic potential of LRRK2 exon 41 skipping via ASO treatment in a preclinical mouse model of Parkinson's disease.
- To assess the efficacy of ASO-induced exon skipping in reducing pathogenic LRRK2 kinase activity and downstream cellular dysfunction.
Main Methods:
- Transgenic mice expressing human wild-type or G2019S LRRK2 were treated with a single intracerebroventricular injection of an ASO designed to induce LRRK2 exon 41 skipping.
- Assessed the impact of ASO treatment on LRRK2 exon 41 skipping, LRRK2 kinase substrate phosphorylation (RAB10), and autophagic markers (LC3B II/I ratios).
Main Results:
- A single intracerebroventricular ASO injection successfully induced LRRK2 exon 41 skipping in treated mice.
- Exon 41 skipping led to a significant decrease in the phosphorylation of LRRK2's substrate, RAB10.
- The ASO treatment reversed LRRK2 kinase-dependent alterations in the LC3B II/I ratio, indicating restoration of autophagic processes.
Conclusions:
- LRRK2 exon 41 skipping is a viable strategy to reduce pathogenic LRRK2 kinase activity in vivo.
- This approach holds significant therapeutic potential for modulating LRRK2-associated Parkinson's disease.
- Targeting LRRK2 splicing represents a promising avenue for developing novel Parkinson's disease treatments.
