PKU is a reversible neurodegenerative process within the nigrostriatum that begins as early as 4 weeks of age in Pah(enu2) mice.
Phenylketonuria (PKU) is a common genetic disorder in humans that arises from deficient activity of phenylalanine hydroxylase (PAH), which catalyzes the conversion of phenylalanine to tyrosine. There is a resultant hyperphenylalanemia with subsequent impairment in cognitive abilities, executive functions and motor coordination. The neuropathogenesis of the disease has not been completely elucidated, however, oxidative stress is considered to be a key feature of the disease process. Hyperphenylalanemia also adversely affects monoaminergic metabolism in the brain. For this reason we chose to evaluate the nigrostriatum of Pah(enu2) mice, to determine if alterations of monoamine metabolism resulted in morphologic nigrostriatal pathology. Furthermore, we believe that recent developments in adeno-associated virus (AAV)-based vectors have greatly increased the potential for long-term gene therapy and may be a viable alternative to dietary treatment for this metabolic disorder. In this study we identified neurodegenerative changes with regenerative responses in the nigrostriatum of Pah(enu2) mice that are consistent with oxidative injury and occurred as early as 4 weeks of age. These neuropathologic changes were reversed following portal vein delivery of a recombinant adeno-associated virus-mouse phenylalanine hydroxylase-woodchuck hepatitis virus post-transcriptional response element (rAAV-mPAH-WPRE) vector to Pah(enu2) mice and corresponded to rapid reduction of serum Phe levels.
Embury
Jennifer E
JE
Department of Biochemistry and Molecular Biology, PO Box 100245, College of Medicine, University of Florida, Gainesville, FL 32610, USA. jembury@ufl.edu
Charron
Catherine E
CE
Martynyuk
Anatoly
A
Zori
Andreas G
AG
Liu
Bin
B
Ali
Syed F
SF
Rowland
Neil E
NE
Laipis
Philip J
PJ
D000594:Amino Acid Oxidoreductases / Q000172:deficiency / Q000235:genetics; D000818:Animals; D015306:Biogenic Monoamines / Q000096:biosynthesis; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods* / Q000639:trends; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D010649:Phenylalanine / Q000378:metabolism; D010661:Phenylketonurias / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D016896:Treatment Outcome
D015306:Biogenic Monoamines; D010649:Phenylalanine; D000594:Amino Acid Oxidoreductases; C022342:phenylalanine oxidase