Pantothenate kinase-associated neurodegeneration (PKAN) is a relentlessly progressive neurological disorder and the most common syndrome among the neurodegeneration with brain iron accumulation (NBIA) disorders. PKAN patients are at a higher risk for a premature death and exhibit a broad clinical spectrum, with affected children exhibiting a more rapid disease progression and a more severe motor involvement compared to adults. There is no effective treatment for PKAN and the lack of a mouse model of the disease is a major obstacle to the development of a cure. PKAN is caused by mutations in PANK2, a gene that is required for the synthesis of coenzyme A (CoA), a universal cofactor essential for lipid synthesis and energy metabolism. Most of the mutations in PANK2 reduce or abolish the activity of the enzyme, leading to the hypothesis that reduced CoA might be the underlying cause of the neurodegeneration in PKAN patients; however, no mouse model of the disease is currently available to investigate the connection between neuronal CoA levels and neurodegeneration, and the molecular mechanisms leading to PKAN remain unknown. Previous attempts to generate a PKAN mouse model have focused on reducing whole-body CoA synthesis or availability by genetic (knocking out every mouse Pank alone or in combination) and/or dietary manipulations. These approaches have produced mice that either do not show signs of neurodegeneration or cannot be used to develop PKAN therapeutics because of their extremely short life-span (18 days) and/or their significantly impaired whole-body metabolism. We recently made significant progress towards the development of a clinically relevant PKAN mouse model by using a novel approach based on the selective degradation of CoA in mouse neurons. To achieve this, we used the combination of an adeno-associated virus (AAV) and a neuron-specific promoter to deliver and over-express a CoA-degrading enzyme, Nudt7cyt, in neurons throughout the brain and spinal cord. Mice expressing Nudt7cyt exhibited a significant reduction in brain CoA and motor coordination compared to the control mice expressing green fluorescent protein (GFP); however, the highly variable transgene expression obtained with the AAV approach makes the connection between CoA and reduced motor coordination difficult to characterize. The objective of this proposal is to improve this strategy by generating transgenic mice with neuron-specific Nudt7cyt expression. These mice will be evaluated with a combination of behavior, motor skill and histological analyses. The results will be correlated with CoA measurements in different brain regions. This novel approach to the generation of a PKAN mouse model will provide a model system to identify CoA-dependent pathways that are disrupted in PKAN disease and a platform to test potential treatments.
Children and adults suffering from pantothenate kinase-associated neurodegeneration (PKAN) exhibit a progressive impairment in movement, cognition and vision, and are at a higher risk for premature death. Although the gene that carries the disease-causing mutations has been identified, the mechanisms that lead to the neurodegeneration remain unknown, and the lack of a mouse model has been a major obstacle to the development of a cure for PKAN. The research proposed herein will fill this gap by generating and characterizing a viable PKAN mouse model to gain insight into the causes of this disease and accelerate ongoing efforts to identify therapeutics to treat it.
| Corbin, Deborah R; Rehg, Jerold E; Shepherd, Danielle L et al. (2017) Excess coenzyme A reduces skeletal muscle performance and strength in mice overexpressing human PANK2. Mol Genet Metab 120:350-362 |
