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Lam, D. ; Williams, R.H. ; Lujan, E.* ; Tanabe, K.* ; Huber, G. ; Saw, N.L.* ; Merl-Pham, J. ; Salminen, A.V. ; Lohse, D. ; Spendiff, S.* ; Plastini, M.J.* ; Zech, M. ; Lochmüller, H.* ; Geerlof, A. ; Hauck, S.M. ; Shamloo, M.* ; Wernig, M.* ; Winkelmann, J.

Collagen VI regulates motor circuit plasticity and motor performance by cannabinoid modulation.

J. Neurosci. 42, 1557-1573 (2022)
Postprint DOI
Open Access Green
Collagen VI is a key component of muscle basement membranes, and genetic variants can cause monogenic muscular dystrophies. Conversely, human genetic studies recently implicated collagen VI in central nervous system function, with variants causing the movement disorder dystonia. To elucidate the neurophysiological role of collagen VI, we generated mice with a truncation of the dystonia-related collagen α3 (VI) (COL6A3) C-terminal domain (CTD). These Col6a3 CTT mice showed a recessive dystonia-like phenotype in both sexes. We found that COL6A3 interacts with the cannabinoid receptor 1 (CB1R) complex in a CTD-dependent manner. Col6a3 CTT mice of both sexes have impaired homeostasis of excitatory input to the basal pontine nuclei (BPN), a motor control hub with dense COL6A3 expression, consistent with deficient endocannabinoid signaling. Aberrant synaptic input in the BPN was normalized by a CB1R agonist, and motor performance in Col6a3 CTT mice of both sexes was improved by CB1R agonist treatment. Our findings identify a readily therapeutically addressable synaptic mechanism for motor control.SIGNIFICANCE STATEMENTDystonia is a movement disorder characterized by involuntary movements. We previously identified genetic variants affecting a specific domain of the COL6A3 protein as a cause of dystonia. Here, we created mice lacking the affected domain and observed an analogous movement disorder. Using a protein interaction screen, we found that the affected COL6A3 domain mediates an interaction with the cannabinoid receptor CB1R. Concordantly, our COL6A3-deficient mice showed a deficit in synaptic plasticity linked to a deficit in cannabinoid signaling. Pharmacological cannabinoid augmentation rescued the motor impairment of the mice. Thus, cannabinoid augmentation could be a promising avenue for treating dystonia, and we have identified a possible molecular mechanism mediating this.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Basal Pontine Nuclei ; Cannabinoid Receptor ; Collagen Vi ; Dystonia ; Endocannabinoid ; Synaptic Homeostasis; Parkinsons-disease; Mutations; Dystonia; Proteome; Endocannabinoids; Projections; Activation; Receptors; Apoptosis; Autophagy
ISSN (print) / ISBN 0270-6474
e-ISSN 1529-2401
Quellenangaben Volume: 42, Issue: 8, Pages: 1557-1573 Article Number: , Supplement: ,
Publisher Society for Neuroscience
Publishing Place 11 Dupont Circle, Nw, Ste 500, Washington, Dc 20036 Usa
Reviewing status Peer reviewed
Grants Muscular Dystrophy Canada
Canada Research Chairs Program (Canada Research Chair in Neuromuscular Genomics and Health)
Canada Foundation for Innovation
Canadian Institutes of Health Research
Deutscher Akademischer Austauschdienst Ruckkehrstipendium
European Research Council (ERC) under the European Union
Deutsche Forschungsgemeinschaft