Differential expression of striatal proteins in a mouse model of DOPA-responsive dystonia reveals shared mechanisms among dystonic disorders

• Type of Material: Article
• Authors: Maria A Briscione, Emory University; Ashok R Dinasarapu, Emory University; Pritha Bagchi, Emory University; Yuping Donsante, Emory University; Kaitlyn M Roman, Emory University; Anthony M Downs, Emory University; Xueliang Fan, Emory University; Jessica Hoehner, Emory University; Hyder Jinnah, Emory University; Ellen Hess, Emory University
• Language: English
• Date: 2021-07-15
• Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ymgme.2021.05.010
• Title of Journal or Parent Work: MOLECULAR GENETICS AND METABOLISM
• Volume: 133
• Issue: 4
• Start Page: 352
• End Page: 361
• Grant/Funding Information: This work was supported by the National Institutes of Health, National Institute of Neurological Disorders and Stroke Grant R01 NS088528, F31 NS103363 and T32 NS007480.
• Keywords: Basal ganglia; ALEXANDER-DISEASE; Dopamine; RECEPTOR-BINDING; Life Sciences & Biomedicine; Genetics & Heredity; DYSFUNCTION; GENE; DEFICIENCY; POINT MUTATION; Endocrinology & Metabolism; Knockin mouse; NEURONS; Research & Experimental Medicine; PLASTICITY; Medicine, Research & Experimental; Proteomics; Mitochondria; Science & Technology; NEUROTRANSMISSION; BASAL GANGLIA

Abstract

Dystonia is characterized by involuntary muscle contractions that cause debilitating twisting movements and postures. Although dysfunction of the basal ganglia, a brain region that mediates movement, is implicated in many forms of dystonia, the underlying mechanisms are unclear. The inherited metabolic disorder DOPA-responsive dystonia is considered a prototype for understanding basal ganglia dysfunction in dystonia because it is caused by mutations in genes necessary for the synthesis of the neurotransmitter dopamine, which mediates the activity of the basal ganglia. Therefore, to reveal abnormal striatal cellular processes and pathways implicated in dystonia, we used an unbiased proteomic approach in a knockin mouse model of DOPA-responsive dystonia, a model in which the striatum is known to play a central role in the expression of dystonia. Fifty-seven of the 1805 proteins identified were differentially regulated in DOPA-responsive dystonia mice compared to control mice. Most differentially regulated proteins were associated with gene ontology terms that implicated either mitochondrial or synaptic dysfunction whereby proteins associated with mitochondrial function were generally over-represented and proteins associated with synaptic function were largely under-represented. Remarkably, nearly 20% of the differentially regulated striatal proteins identified in our screen are associated with pathogenic variants that cause inherited disorders with dystonia as a sign in humans suggesting shared mechanisms across many different forms of dystonia.