Modulation of striatal cAMP levels: A key pathway in the treatment of hyperkinetic movement disorders

Ruiyi Yuan; Emmanuel Roze; Mohamed Doulazmi; Caroline Dubacq; Sophie Longueville; Marine Delmas; Boutheyna Khelaifia; Julia Micaux; Yuki Nakamura; Marco Romanato; Clément Tarrano; Noël Zahr; Assunta Pelosi; Marie Vidailhet; Jean-Antoine Girault; Aurélie Méneret; Denis Hervé; Louise-Laure Mariani

doi:10.1016/j.isci.2025.114457

Modulation of striatal cAMP levels: A key pathway in the treatment of hyperkinetic movement disorders

iScience. 2025 Dec 18;29(2):114457. doi: 10.1016/j.isci.2025.114457. eCollection 2026 Feb 20.

Authors

Ruiyi Yuan¹, Emmanuel Roze^{1

2}, Mohamed Doulazmi³, Caroline Dubacq¹, Sophie Longueville⁴, Marine Delmas^{1

4}, Boutheyna Khelaifia^{1

4}, Julia Micaux^{1

4}, Yuki Nakamura^{4

5}, Marco Romanato¹, Clément Tarrano^{1

2

6}, Noël Zahr⁷, Assunta Pelosi¹, Marie Vidailhet^{1

2}, Jean-Antoine Girault^{1

4}, Aurélie Méneret^{1

2}, Denis Hervé^{1

4}, Louise-Laure Mariani^{1

2

4

7}

Affiliations

¹ Sorbonne University, Paris Brain Institute, INSERM, CNRS, Paris, France.
² AP-HP, Pitié-Salpêtrière Hospital, DMU Neuroscience, Paris, France.
³ Sorbonne University, INSERM, CNRS, Institute of Biology Paris-Seine, Paris, France.
⁴ Sorbonne University, Fer à Moulin Institute, INSERM, Paris, France.
⁵ Department of Pharmacology, Kurume University School of Medicine, Kurume, Fukuoka, Japan.
⁶ AP-HP, Saint-Antoine Hospital, Department of Neurophysiology, Paris, France.
⁷ AP-HP, Pitié-Salpêtrière Hospital, Department of Pharmacology, Paris, France.

Abstract

Hyperkinetic movement disorders, like dystonia, chorea, myoclonus, dyskinesia, and tremor, can be extremely disabling, impairing quality of life. Our translational approach in humans and mice investigates the link between cyclic AMP (cAMP) signaling pathway alterations in striatal neurons and hyperkinetic movement disorders. ADCY5 encodes adenylyl cyclase 5, key enzyme for striatal cAMP synthesis. Pathogenic variants result in mixed hyperkinetic movement disorders (MxMD-ADCY5). We prove caffeine therapeutic effect in a prospective trial in two patients with MxMD-ADCY5 and generated an Adcy5 ^R419W mouse model harboring the most frequent human pathogenic variant to understand underlying mechanisms. In patients, movements' severity is increased in absence of caffeine. In mice, caffeine improves motor symptoms through adenosine A_2A receptor blockade. Mutation increases cAMP signaling in striatal projection neurons, an effect selectively corrected by A_2A receptor antagonism in indirect pathway neurons. Fine modulation of neuronal cAMP levels represents a key target to treat hyperkinetic disorders, especially dystonia/dyskinesia.

Keywords: Molecular biology; Neuroscience; Pharmacology.