GRK2-Targeted Knockdown as Therapy for Multiple System Atrophy

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Insulin Resistance*
  • Insulins* / therapeutic use
  • Mice
  • Mice, Transgenic
  • MicroRNAs*
  • Movement Disorders*
  • Multiple System Atrophy* / drug therapy
  • Multiple System Atrophy* / therapy
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism


  • alpha-Synuclein
  • MicroRNAs
  • Insulins