Dystonia pathogenesis: role of collagen VI

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The goal of the proposed project is to gain a better understanding of the pathogenic basis of dystonia. Dystonia is a movement disorder characterized by involuntary abnormal movements and postures. We recently identified mutations in COL6A3, encoding a collagen VI subunit, as one of the first known causes of recessively inherited dystonia. We subsequently generated a mouse loss-of-function model, which displays dystonia-like motor abnormalities. To understand how COL6A3 is involved in dystonia pathogenesis, we propose a series of molecular, cellular, and systems-level investigations. First, we will identify the binding partners of secreted COL6A3 in mouse brain lysates, using immunoprecipitation and mass spectrometry. To delineate brain regions mediating the effects of COL6A3, we will perform comprehensive histological expression analysis across mouse development. Finally, we will investigate the effects of Col6a3 deficiency on axonal architecture in mice using high-throughput pan-axonal labeling in intact optically cleared brains. Collectively, these studies will illuminate how COL6A3, via binding to specific partners, influences brain wiring, and how its disruption causes dystonia. More generally, this will unravel the previously unexplored role of extracellular matrix in dystonia. These insights into a completely novel disease mechanism are likely to identify new therapeutic targets.