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.Read less <