Single gene disorders provide valuable insights into mechanisms of common diseases and represent highly tractable systems for developing rational therapeutics. PKAN (pantothenate kinase-associated neurodegeneration) is a profoundly disabling and painful genetic disorder causing dystonia, parkinsonism, blindness and early death in children and adults. Currently there are no disease-modifying treatments. Our long-term goals are to elucidate pathogenesis and develop a treatment for this lethal disease. PKAN is an inborn error of coenzyme A (CoA) synthesis that results in neurodegeneration with brain iron accumulation. Though brain iron accumulation is a hallmark of PKAN, the link between defective CoA metabolism, iron dyshomeostasis, and neurodegeneration has remained unclear. The lack of a robust mammalian disease model of PKAN has limited research progress and still represents a critical research resource for the field. Using a mouse knock-out of Pank2 and a new approach to separating disease-vulnerable from disease-protected brain regions, we have discovered a set of disease-relevant brain abnormalities. This molecular `signature' includes markers of perturbed CoA, iron, and dopamine metabolism and oxidative phosphorylation only in the disease-vulnerable regions. We propose to investigate this powerful model with the goals to delineate the molecular pathogenesis of PKAN, to demonstrate efficacy of a candidate therapeutic, and to discover biomarkers that can be translated for use in human interventional trials.
Few examples exist of a neurodegenerative disease in which the key elements of pathogenesis are known and can be reversed by a rational therapeutic. In this application we propose 1) to delineate a new mechanism of pathogenesis for pantothenate kinase-associated neurodegeneration (PKAN), a severely disabling single gene disorder; 2) to investigate a highly relevant mammalian disease model that recapitulates key elements of PKAN; and 3) to strengthen evidence for efficacy of a rational therapeutic for PKAN.