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.