GRK2‐ Targeted Knockdown as Therapy for Multiple System Atrophy

Miguel Lopez‐Cuina, Paul Guérin, Nathalie Dutheil, Christelle Martin, Thierry Leste Lasserre, Pierre‐Olivier Fernagut, Wassilios G. Meissner, Erwan Bezard
Movement Disorders. 2023-04-24; :
DOI: 10.1002/mds.29422

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Lopez-Cuina M(1)(2)(3)(4), Guérin P(1)(2), Dutheil N(1)(2), Martin C(5), Lasserre TL(6), Fernagut PO(7), Meissner WG(1)(2)(8)(9), Bezard E(1)(2).

Author information:
(1)Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
(2)CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
(3)Neurology Department, Hospital Universitario Reina Sofía, Córdoba, Spain.
(4)Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain.
(5)Univ. de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, Bordeaux, France.
(6)Univ. Bordeaux, INSERM, PUMA, Neurocentre Magendie, U1215, Bordeaux, France.
(7)Université de Poitiers, Laboratoire de Neurosciences Expérimentales et Cliniques, INSERM UMR_S 1084, Poitiers, France.
(8)CHU Bordeaux, Service de Neurologie des Maladies Neurodégénératives, IMNc, Bordeaux, France.
(9)Department of Medicine, University of Otago, Christchurch, and New Zealand Brain Research Institute, Christchurch, New Zealand.

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 anestablished 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.

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