Retinoic acid receptor beta protects striatopallidal medium spiny neurons from mitochondrial dysfunction and neurodegeneration.
Fiche publication
Date publication
février 2022
Journal
Progress in neurobiology
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DOLLE Pascal, Dr KREZEL Wojciech, Pr GENY Bernard
Tous les auteurs :
Ciancia M, Rataj-Baniowska M, Zinter N, Baldassarro VA, Fraulob V, Charles AL, Alvarez R, Muramatsu SI, de Lera AR, Geny B, Dollé P, Niewiadomska-Cimicka A, Krezel W
Lien Pubmed
Résumé
Retinoic acid is a powerful regulator of brain development, however its postnatal functions only start to be elucidated. We show that retinoic acid receptor beta (RARβ), is involved in neuroprotection of striatopallidal medium spiny neurons (spMSNs), the cell type affected in different neuropsychiatric disorders and particularly prone to degenerate in Huntington disease (HD). Accordingly, the number of spMSNs was reduced in the striatum of adult Rarβ mice, which may result from mitochondrial dysfunction and neurodegeneration. Mitochondria morphology was abnormal in mutant mice whereas in cultured striatal Rarβ neurons mitochondria displayed exacerbated depolarization, and fragmentation followed by cell death in response to glutamate or thapsigargin-induced calcium increase. In vivo, Rarβ spMSNs were also more vulnerable to the mitochondrial toxin 3-nitropropionic acid (3NP), known to induce HD symptoms in human and rodents. In contrary, an RARβ agonist, UVI2062, decreased glutamate-induced toxicity in primary striatal neurons in vitro, and diminished mitochondrial dysfunction, spMSN cell death and motor deficits induced in wild type mice by 3NP. We demonstrate that the striatopallidal pathway is compromised in Rarβ mice and associated with HD-like motor abnormalities. Importantly, similar motor abnormalities and selective reduction of spMSNs were induced by striatal or spMSN-specific inactivation of RARβ, further supporting a neuroprotective role of RARβ in postnatal striatum.
Mots clés
Huntington’s disease, medium spiny neurons, mice models of movement disorders, mitochondria, motor behavior, nuclear hormone receptors, retinoic acid receptors, striatum
Référence
Prog Neurobiol. 2022 Feb 10;:102246