4 '-Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN

Pantothenate kinase-associated neurodegeneration (PKAN) is an inborn error of CoA metabolism causing dystonia, parkinsonism, and brain iron accumulation. Lack of a good mammalian model has impeded studies of pathogenesis and development of rational therapeutics. We took a new approach to investigating an existing mouse mutant of Pank2 and found that isolating the disease-vulnerable brain revealed regional perturbations in CoA metabolism, iron homeostasis, and dopamine metabolism and functional defects in complex I and pyruvate dehydrogenase. Feeding mice a CoA pathway intermediate, 4 '-phosphopantetheine, normalized levels of the CoA-, iron-, and dopamine-related biomarkers as well as activities of mitochondrial enzymes. Human cell changes also were recovered by 4 '-phosphopantetheine. We can mechanistically link a defect in CoA metabolism to these secondary effects via the activation of mitochondrial acyl carrier protein, which is essential to oxidative phosphorylation, iron-sulfur cluster biogenesis, and mitochondrial fatty acid synthesis. We demonstrate the fidelity of our model in recapitulating features of the human disease. Moreover, we identify pharmacodynamic biomarkers, provide insights into disease pathogenesis, and offer evidence for 4 '-phosphopantetheine as a candidate therapeutic for PKAN

Identifying the Neural Mechanisms of Approach Behavior: Studying the Role of Superior Colliculus During Prey-capture Behavior in the Mouse

43 pages. A thesis presented to the Department of Chemistry and Biochemistry and the Clark Honors College of the University of Oregon in partial fulfillment of the requirements for degree of Bachelor of Science, Spring 2017In mammalian brains, there are two areas that process information important for image formation and goal directed visual behavior: primary visual cortex (V1), and the superior colliculus (SC). However, it is unclear how these regions support visually driven orienting and approach behaviors towards naturally rewarding stimuli. In this study, we seek to identify how the SC directs visual behavior using a mouse model of prey-capture behavior. Here, we investigate whether natural prey-capture behavior in mice is affected when regions of SC are silenced through injections of the GABAA-R agonist, muscimol, and through the use of pharmacogenetics known as DREADDs. We found that inhibition of the SC decreases the accuracy of approaches to prey and increases time to capture. Our studies so far indicate that inhibition of SC impairs ethological prey-capture behavior in mice. An understanding of the specific circuitry underlying visually guided behaviors directed towards rewarding stimuli will give insight into neurological disorders such as PTSD and addiction, where processes of orienting and approach are affected

Identifying the neural mechanism of approach behavior: studying the role of superior colliculus during prey-capture behavior

Single page posterIn mammalian brains, there are two areas that process information important for image formation and goal directed visual behavior: primary visual cortex (V1), and the superior colliculus (SC). However, it is unclear how these regions support visually driven orienting and approach behaviors towards naturally rewarding stimuli. In this study, we seek to identify how the SC directs visual behavior using a mouse model of prey-capture behavior. Here, we investigate whether natural prey-capture behavior in mice is affected when regions of SC are silenced through injections of the GABAA-R agonist, muscimol, and through the use of pharmacogenetics known as DREADDs. We found that inhibition of the SC decreases the accuracy of approaches to prey and increases time to capture. Our studies so far indicate that inhibition of SC impairs ethological prey-capture behavior in mice. An understanding of the specific circuitry underlying visually guided behaviors directed towards rewarding stimuli will give insight into neurological disorders such as PTSD and addiction, where processes of orienting and approach are affected.National Institutes of Health Grants 1RO1EY023337 and 1DP2EY023190 (C.M.N.) and 1F32EY024179 (J.L.H.)

Autosomal dominant mitochondrial membrane protein-associated neurodegeneration (MPAN)

Background Mitochondrial membrane protein-associated neurodegeneration (MPAN) is caused by pathogenic sequence variants in C19orf12. Autosomal recessive inheritance has been demonstrated. We present evidence of autosomal dominant MPAN and propose a mechanism to explain these cases. Methods Two large families with apparently dominant MPAN were investigated; additional singleton cases of MPAN were identified. Gene sequencing and multiplex ligation-dependent probe amplification were used to characterize the causative sequence variants in C19orf12. Post-mortem brain from affected subjects was examined. Results In two multi-generation non-consanguineous families, we identified different nonsense sequence variations in C19orf12 that segregate with the MPAN phenotype. Brain pathology was similar to that of autosomal recessive MPAN. We additionally identified a preponderance of cases with single heterozygous pathogenic sequence variants, including two with de novo changes. Conclusions We present three lines of clinical evidence to demonstrate that MPAN can manifest as a result of only one pathogenic C19orf12 sequence variant. We propose that truncated C19orf12 proteins, resulting from nonsense variants in the final exon in our autosomal dominant cohort, impair function of the normal protein produced from the non-mutated allele via a dominant negative mechanism and cause loss of function. These findings impact the clinical diagnostic evaluation and counseling