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. 2023 Jul;38(7):1336-1340.
doi: 10.1002/mds.29422. Epub 2023 Apr 24.

GRK2-Targeted Knockdown as Therapy for Multiple System Atrophy

Miguel Lopez-Cuina  1   2   3   4 , Paul Guérin  1   2 , Nathalie Dutheil  1   2 , Christelle Martin  5 , Thierry Leste Lasserre  6 , Pierre-Olivier Fernagut  7 , Wassilios G Meissner  1   2   8   9 , Erwan Bezard  1   2
Affiliations

GRK2-Targeted Knockdown as Therapy for Multiple System Atrophy

Miguel Lopez-Cuina et al. Mov Disord. 2023 Jul.

Abstract

Background: Multiple system atrophy (MSA) is a sporadic adult-onset rare neurodegenerative synucleinopathy for which counteracting central nervous system insulin resistance bears the potential of being neuroprotective. G-protein-(heterotrimeric guanine nucleotide-binding protein)-coupled receptor kinase 2 (GRK2) is emerging as a physiologically relevant inhibitor of insulin signaling.

Objectives: We tested whether lowering brain GRK2 abundance may reverse insulin-resistance.

Methods: We lowered brain GRK2 abundance through viral-mediated delivery of a GRK2-specific miRNA and quantified the reversion of a developing or an established insulin-resistant phenotype using the transgenic PLP-SYN mouse model of MSA.

Results: Viral vector delivery of a GRK2 miRNA demonstrated a neuroprotective capacity when administered (1) in utero intracerebroventricularly in developing PLP-SYN mice and (2) intrastriatally in adult PLP-SYN mice. Decreased striatal GRK2 levels correlated in both designs with neuroprotection of the substantia nigra dopamine neurons, reduction in high-molecular-weight species of α-synuclein, and reduced insulin resistance.

Conclusions: These data support GRK2 as a potential therapeutic target in MSA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: in utero; insulin resistance; synucleinopathy.

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References

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