Abstract
BackgroundPantothenate kinase-associated neurodegeneration, PKAN, is an inherited disorder characterized by progressive impairment in motor coordination and caused by mutations in PANK2, a human gene that encodes one of four pantothenate kinase (PanK) isoforms. PanK initiates the synthesis of coenzyme A (CoA), an essential cofactor that plays a key role in energy metabolism and lipid synthesis. Most of the mutations in PANK2 reduce or abolish the activity of the enzyme. This evidence has led to the hypothesis that lower 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. Indeed, genetic and/or dietary manipulations aimed at reducing whole-body CoA synthesis have not produced a desirable PKAN model, and this has greatly hindered the discovery of a treatment for the disease.Objective, Methods, Results and ConclusionsCellular CoA levels are tightly regulated by a balance between synthesis and degradation. CoA degradation is catalyzed by two peroxisomal nudix hydrolases, Nudt7 and Nudt19. In this study we sought to reduce neuronal CoA in mice through the alternative approach of increasing Nudt7-mediated CoA degradation. This was achieved by combining the use of an adeno-associated virus-based expression system with the synapsin (Syn) promoter. We show that mice with neuronal overexpression of a cytosolic version of Nudt7 (scAAV9-Syn-Nudt7cyt) exhibit a significant decrease in brain CoA levels in conjunction with a reduction in motor coordination. These results strongly support the existence of a link between CoA levels and neuronal function and show that scAAV9-Syn-Nudt7cyt mice can be used to model PKAN.
Highlights
Syndromes of neurodegeneration with brain iron accumulation (NBIAs) are rare, inherited and genetically defined disorders characterized by an accumulation of iron in the brain and progressive impairment in movement, cognition and vision [1]
Cellular coenzyme A (CoA) levels are tightly regulated by a balance between synthesis and degradation
Pantothenate kinase-associated neurodegeneration (PKAN) is the most common syndrome among the NBIA disorders, shows an autosomal recessive inheritance and it is caused by mutations in PANK2 [2], a gene that encodes one of four pantothenate kinase (PanK) isoforms
Summary
Syndromes of neurodegeneration with brain iron accumulation (NBIAs) are rare, inherited and genetically defined disorders characterized by an accumulation of iron in the brain and progressive impairment in movement, cognition and vision [1]. Unlike the murine and other mammalian PanK2 homologs, human PANK2 possesses a full length mitochondrial localization signal and localizes to the mitochondria and the nucleus [5, 6] This enzyme is a major PanK isoform in human brain, and PKAN symptoms are predominantly limited to the central nervous system with only modest metabolic alterations reported for some PKAN patients [7, 8]. Most of the disease-causing mutations in PANK2 significantly reduce or abolish the activity of the enzyme [9, 10] This evidence, combined with the established importance of CoA for mitochondrial bioenergetics and cellular metabolism, suggests that a reduction in CoA and the consequent impairment in neuronal function might be the underlying causes of the neurodegeneration in PKAN patients. Genetic and/or dietary manipulations aimed at reducing whole-body CoA synthesis have not produced a desirable PKAN model, and this has greatly hindered the discovery of a treatment for the disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
