The Experts below are selected from a list of 186 Experts worldwide ranked by ideXlab platform
Suzanne Jackowski - One of the best experts on this subject based on the ideXlab platform.
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Localization and regulation of mouse Pantothenate Kinase 2
FEBS letters, 2007Co-Authors: Roberta Leonardi, Yong-mei Zhang, Charles O. Rock, Athanasios Lykidis, Suzanne JackowskiAbstract:Coenzyme A (CoA) biosynthesis is initiated by Pantothenate Kinase (PanK) and CoA levels are controlled through differential expression and feedback regulation of PanK isoforms. PanK2 is a mitochondrial protein in humans, but comparative genomics revealed that acquisition of a mitochondrial targeting signal was limited to primates. Human and mouse PanK2 possessed similar biochemical properties, with inhibition by acetyl-CoA and activation by palmitoylcarnitine. Mouse PanK2 localized in the cytosol, and the expression of PanK2 was higher in human brain compared to mouse brain. Differences in expression and subcellular localization should be considered in developing a mouse model for human PanK2 deficiency.
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activation of human mitochondrial Pantothenate Kinase 2 by palmitoylcarnitine
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Roberta Leonardi, Suzanne Jackowski, Charles O. Rock, Yong-mei ZhangAbstract:The human isoform 2 of Pantothenate Kinase (PanK2) is localized to the mitochondria, and mutations in this protein are associated with a progressive neurodegenerative disorder. PanK2 inhibition by acetyl-CoA is so stringent (IC50 < 1 μM) that it is unclear how the enzyme functions in the presence of intracellular CoA concentrations. Palmitoylcarnitine was discovered to be a potent activator of PanK2 that functions to competitively antagonize acetyl-CoA inhibition. Acetyl-CoA was a competitive inhibitor of purified PanK2 with respect to ATP. The interaction between PanK2 and acetyl-CoA was stable enough that a significant proportion of the purified protein was isolated as the PanK2·acetyl-CoA complex. The long-chain acylcarnitine activation of PanK2 explains how PanK2 functions in vivo, by providing a positive regulatory mechanism to counteract the negative regulation of PanK2 activity by acetyl-CoA. Our results suggest that PanK2 is located in the mitochondria to sense the levels of palmitoylcarnitine and up-regulate CoA biosynthesis in response to an increased mitochondrial demand for the cofactor to support β-oxidation.
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Biochemical properties of human Pantothenate Kinase 2 isoforms and mutations linked to Pantothenate Kinase-associated neurodegeneration.
The Journal of biological chemistry, 2005Co-Authors: Yong-mei Zhang, Charles O. Rock, Suzanne JackowskiAbstract:The PANK2 gene encodes the human Pantothenate Kinase 2 protein isoforms, and PANK2 mutations are linked to Pantothenate Kinase-associated neurodegeneration. Two PanK2 protein forms are proteolytically processed to form a mitochondrially localized, mature PanK2. Another isoform arose from a proposed initiation at a leucine codon and was not processed further. The fifth isoform was postulated to arise from an alternative splicing event and was found to encode an inactive protein. Fourteen mutant PanK2 proteins with single amino acid substitutions, associated with either early or late onset disease, were evaluated for activity. The PanK2(G521R), the most frequent mutation in Pantothenate Kinase-associated neurodegeneration, was devoid of activity and did not fold properly. However, nine of the mutant proteins associated with disease possessed catalytic activities that were indistinguishable from wild type, including the frequently encountered PanK2(T528M) missense mutation. PanK2 was extremely sensitive to feedback inhibition by CoA thioesters (IC50 values between 250 and 500 nM), and the regulation of the active PanK2 mutants was comparable with that of the wild-type protein. Coexpression of the PanK2(G521R) and wild-type PanK2 did not interfere with wild-type enzyme activity, arguing against a dominant negative effect of the PanK2(G521R) mutation in heterozygous patients. These data described the unique biochemical features of the PanK2 isoforms and suggested that catalytic defects may not be the sole cause for the neurodegenerative phenotype.
Jane Gitschier - One of the best experts on this subject based on the ideXlab platform.
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deficiency of Pantothenate Kinase 2 pank2 in mice leads to retinal degeneration and azoospermia
Human Molecular Genetics, 2005Co-Authors: Ying Ming Kuo, Jacque L Duncan, Shawn K Westaway, Haidong Yang, George Nune, Susan J Hayflick, Jane GitschierAbstract:Pantothenate Kinase-associated neurodegeneration (PKAN, formerly known as Hallervorden-Spatz syndrome) is a rare but devastating neurodegenerative disorder, resulting from an inherited defect in coenzyme A biosynthesis. As pathology in the human condition is limited to the central nervous system, specifically the retina and globus pallidus, we have generated a mouse knock-out of the orthologous murine gene (Pank2) to enhance our understanding of the mechanisms of disease and to serve as a testing ground for therapies. Over time, the homozygous null mice manifest retinal degeneration, as evidenced by electroretinography, light microscopy and pupillometry response. Specifically, Pank2 mice show progressive photoreceptor decline, with significantly lower scotopic a- and b-wave amplitudes, decreased cell number and disruption of the outer segment and reduced pupillary constriction response when compared with those of wild-type littermates. Additionally, the homozygous male mutants are infertile due to azoospermia, a condition that was not appreciated in the human. Arrest occurs in spermiogenesis, with complete absence of elongated and mature spermatids. In contrast to the human, however, no changes were observed in the basal ganglia by MRI or by histological exam, nor were there signs of dystonia, even after following the mice for one year. Pank2 mice are 20% decreased in weight when compared with their wild-type littermates; however, dysphagia was not apparent. Immunohistochemistry shows staining consistent with localization of Pank2 to the mitochondria in both the retina and the spermatozoa.
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genetic clinical and radiographic delineation of hallervorden spatz syndrome
The New England Journal of Medicine, 2003Co-Authors: Susan J Hayflick, Shawn K Westaway, Barbara Levinson, Bing Zhou, Monique A Johnson, Katherine H L Ching, Jane GitschierAbstract:Background Hallervorden–Spatz syndrome is an autosomal recessive disorder characterized by dystonia, parkinsonism, and iron accumulation in the brain. Many patients with this disease have mutations in the gene encoding Pantothenate Kinase 2 (PANK2); these patients are said to have Pantothenate Kinase–associated neurodegeneration. In this study, we compared the clinical and radiographic features of patients with Hallervorden–Spatz syndrome with and without mutations in PANK2. Methods One hundred twenty-three patients from 98 families with a diagnosis of Hallervorden–Spatz syndrome were classified on the basis of clinical assessment as having classic disease (characterized by early onset with rapid progression) or atypical disease (later onset with slow progression). Their genomic DNA was sequenced for PANK2 mutations. Results All patients with classic Hallervorden–Spatz syndrome and one third of those with atypical disease had PANK2 mutations. Whereas almost all mutations in patients with atypical disease ...
Yong-mei Zhang - One of the best experts on this subject based on the ideXlab platform.
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Localization and regulation of mouse Pantothenate Kinase 2
FEBS letters, 2007Co-Authors: Roberta Leonardi, Yong-mei Zhang, Charles O. Rock, Athanasios Lykidis, Suzanne JackowskiAbstract:Coenzyme A (CoA) biosynthesis is initiated by Pantothenate Kinase (PanK) and CoA levels are controlled through differential expression and feedback regulation of PanK isoforms. PanK2 is a mitochondrial protein in humans, but comparative genomics revealed that acquisition of a mitochondrial targeting signal was limited to primates. Human and mouse PanK2 possessed similar biochemical properties, with inhibition by acetyl-CoA and activation by palmitoylcarnitine. Mouse PanK2 localized in the cytosol, and the expression of PanK2 was higher in human brain compared to mouse brain. Differences in expression and subcellular localization should be considered in developing a mouse model for human PanK2 deficiency.
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activation of human mitochondrial Pantothenate Kinase 2 by palmitoylcarnitine
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Roberta Leonardi, Suzanne Jackowski, Charles O. Rock, Yong-mei ZhangAbstract:The human isoform 2 of Pantothenate Kinase (PanK2) is localized to the mitochondria, and mutations in this protein are associated with a progressive neurodegenerative disorder. PanK2 inhibition by acetyl-CoA is so stringent (IC50 < 1 μM) that it is unclear how the enzyme functions in the presence of intracellular CoA concentrations. Palmitoylcarnitine was discovered to be a potent activator of PanK2 that functions to competitively antagonize acetyl-CoA inhibition. Acetyl-CoA was a competitive inhibitor of purified PanK2 with respect to ATP. The interaction between PanK2 and acetyl-CoA was stable enough that a significant proportion of the purified protein was isolated as the PanK2·acetyl-CoA complex. The long-chain acylcarnitine activation of PanK2 explains how PanK2 functions in vivo, by providing a positive regulatory mechanism to counteract the negative regulation of PanK2 activity by acetyl-CoA. Our results suggest that PanK2 is located in the mitochondria to sense the levels of palmitoylcarnitine and up-regulate CoA biosynthesis in response to an increased mitochondrial demand for the cofactor to support β-oxidation.
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Biochemical properties of human Pantothenate Kinase 2 isoforms and mutations linked to Pantothenate Kinase-associated neurodegeneration.
The Journal of biological chemistry, 2005Co-Authors: Yong-mei Zhang, Charles O. Rock, Suzanne JackowskiAbstract:The PANK2 gene encodes the human Pantothenate Kinase 2 protein isoforms, and PANK2 mutations are linked to Pantothenate Kinase-associated neurodegeneration. Two PanK2 protein forms are proteolytically processed to form a mitochondrially localized, mature PanK2. Another isoform arose from a proposed initiation at a leucine codon and was not processed further. The fifth isoform was postulated to arise from an alternative splicing event and was found to encode an inactive protein. Fourteen mutant PanK2 proteins with single amino acid substitutions, associated with either early or late onset disease, were evaluated for activity. The PanK2(G521R), the most frequent mutation in Pantothenate Kinase-associated neurodegeneration, was devoid of activity and did not fold properly. However, nine of the mutant proteins associated with disease possessed catalytic activities that were indistinguishable from wild type, including the frequently encountered PanK2(T528M) missense mutation. PanK2 was extremely sensitive to feedback inhibition by CoA thioesters (IC50 values between 250 and 500 nM), and the regulation of the active PanK2 mutants was comparable with that of the wild-type protein. Coexpression of the PanK2(G521R) and wild-type PanK2 did not interfere with wild-type enzyme activity, arguing against a dominant negative effect of the PanK2(G521R) mutation in heterozygous patients. These data described the unique biochemical features of the PanK2 isoforms and suggested that catalytic defects may not be the sole cause for the neurodegenerative phenotype.
Susan J Hayflick - One of the best experts on this subject based on the ideXlab platform.
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t2 and fse mri distinguishes four subtypes of neurodegeneration with brain iron accumulation
Neurology, 2008Co-Authors: Alisdair Mcneill, Patrick F. Chinnery, Susan J Hayflick, D Birchall, Allison Gregory, J F Schenk, Earl A Zimmerman, Huifang Shang, Hiroaki MiyajimaAbstract:Iron accumulates within the basal ganglia and dentate nuclei during normal aging.1 More intense iron deposition has been demonstrated within the substantia nigra in Parkinson disease, and structures affected by β amyloid plaques in Alzheimer disease, implicating iron deposition in the pathogenesis of common neurodegenerative diseases, possibly through increased oxidative stress.2,3 Direct evidence supporting a causal role for iron deposition in neurodegenerative conditions comes from a group of genetic disorders termed neurodegeneration with brain iron accumulation (NBIA), in which a variety of genetic defects in iron metabolism lead to brain iron accumulation with neuronal death in the affected brain regions.4 Four subtypes of NBIA have been defined at the molecular genetic level. Pantothenate Kinase associated neurodegeneration (PKAN, NBIA type one, MIM 234200), formerly known as Hallervorden-Spatz syndrome, is caused by mutation of the Pantothenate Kinase 2 gene (PANK2).5 Infantile neuroaxonal dystrophy (INAD, MIM 256600) is a recessive disorder with psychomotor regression due to mutations in PLA2G6.6 Mutations of the ferritin light chain gene (FTL1) cause the adult onset autosomal dominant movement disorder neuroferritinopathy (FTL, NBIA type two, hereditary ferritinopathy, MIM 606159).7 A further form of NBIA is aceruloplasminemia (aCp, MIM 604290), an autosomal recessive ceruloplasmin deficiency which results in iron deposition in the reticuloendothelial system and brain, presenting with diabetes and an extrapyramidal movement disorder in adult life.8 Extensive phenotypic overlap presents a major challenge in the clinical diagnosis of different subtypes of NBIA, particularly in the early stages. Although molecular genetic testing can provide the definitive diagnosis, comprehensive testing is only available on a research basis, and the genetic defect remains undefined in a large subgroup of patients with so-called NBIA of unknown cause. A reliable clinical investigation capable of predicting the genetic diagnosis would be useful to inform genetic counseling, predict the disease course, and ensure appropriate enrollment in clinical trials of new treatments. Dramatic evidence of focal brain iron accumulation on brain imaging is usually the first indication of NBIA, but the features distinguishing the different subtypes have yet to be defined.
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deficiency of Pantothenate Kinase 2 pank2 in mice leads to retinal degeneration and azoospermia
Human Molecular Genetics, 2005Co-Authors: Ying Ming Kuo, Jacque L Duncan, Shawn K Westaway, Haidong Yang, George Nune, Susan J Hayflick, Jane GitschierAbstract:Pantothenate Kinase-associated neurodegeneration (PKAN, formerly known as Hallervorden-Spatz syndrome) is a rare but devastating neurodegenerative disorder, resulting from an inherited defect in coenzyme A biosynthesis. As pathology in the human condition is limited to the central nervous system, specifically the retina and globus pallidus, we have generated a mouse knock-out of the orthologous murine gene (Pank2) to enhance our understanding of the mechanisms of disease and to serve as a testing ground for therapies. Over time, the homozygous null mice manifest retinal degeneration, as evidenced by electroretinography, light microscopy and pupillometry response. Specifically, Pank2 mice show progressive photoreceptor decline, with significantly lower scotopic a- and b-wave amplitudes, decreased cell number and disruption of the outer segment and reduced pupillary constriction response when compared with those of wild-type littermates. Additionally, the homozygous male mutants are infertile due to azoospermia, a condition that was not appreciated in the human. Arrest occurs in spermiogenesis, with complete absence of elongated and mature spermatids. In contrast to the human, however, no changes were observed in the basal ganglia by MRI or by histological exam, nor were there signs of dystonia, even after following the mice for one year. Pank2 mice are 20% decreased in weight when compared with their wild-type littermates; however, dysphagia was not apparent. Immunohistochemistry shows staining consistent with localization of Pank2 to the mitochondria in both the retina and the spermatozoa.
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genetic clinical and radiographic delineation of hallervorden spatz syndrome
The New England Journal of Medicine, 2003Co-Authors: Susan J Hayflick, Shawn K Westaway, Barbara Levinson, Bing Zhou, Monique A Johnson, Katherine H L Ching, Jane GitschierAbstract:Background Hallervorden–Spatz syndrome is an autosomal recessive disorder characterized by dystonia, parkinsonism, and iron accumulation in the brain. Many patients with this disease have mutations in the gene encoding Pantothenate Kinase 2 (PANK2); these patients are said to have Pantothenate Kinase–associated neurodegeneration. In this study, we compared the clinical and radiographic features of patients with Hallervorden–Spatz syndrome with and without mutations in PANK2. Methods One hundred twenty-three patients from 98 families with a diagnosis of Hallervorden–Spatz syndrome were classified on the basis of clinical assessment as having classic disease (characterized by early onset with rapid progression) or atypical disease (later onset with slow progression). Their genomic DNA was sequenced for PANK2 mutations. Results All patients with classic Hallervorden–Spatz syndrome and one third of those with atypical disease had PANK2 mutations. Whereas almost all mutations in patients with atypical disease ...
Patrick F. Chinnery - One of the best experts on this subject based on the ideXlab platform.
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Neurodegeneration with brain iron accumulation.
Handbook of clinical neurology, 2011Co-Authors: Alisdair Mcneill, Patrick F. ChinneryAbstract:Neurodegenerative disorders with brain iron accumulation (NBIA) are a clinically and genetically heterogeneous group of conditions in which there is neurodegeneration accompanied by elevated levels of brain iron. NBIA is frequently of genetic etiology, but may be secondary to an acquired systemic or neurological disease. Mutations in the ferritin light chain cause an adult-onset autosomal-dominant choreiform movement disorder termed neuroferritinopathy. Homozygous mutations in the ceruloplasmin gene cause aceruloplasminemia, which is characterized by the triad of diabetes, retinopathy, and a neurological disorder in mid adulthood. Mutations in Pantothenate Kinase 2 (PANK2) and phospholipase A2 (PLA2G6) cause recessive, childhood-onset extrapyramidal disorders termed Pantothenate Kinase-associated neurodegeneration (PKAN) and infantile neuroaxonal dystrophy (INAD), respectively. There is considerable phenotypic overlap between these conditions. The most useful investigation in suspected NBIA is brain magnetic resonance imaging, which can identify pathological iron deposition and distinguish between genotypes. Iron depletion therapy has been demonstrated to be successful in aceruloplasminemia, but not neuroferritinopathy, PKAN, or INAD. The presentation of NBIA overlaps with the more common adult movement disorders and pediatric neurometabolic conditions, and a high index of suspicion is required to make a correct diagnosis.
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t2 and fse mri distinguishes four subtypes of neurodegeneration with brain iron accumulation
Neurology, 2008Co-Authors: Alisdair Mcneill, Patrick F. Chinnery, Susan J Hayflick, D Birchall, Allison Gregory, J F Schenk, Earl A Zimmerman, Huifang Shang, Hiroaki MiyajimaAbstract:Iron accumulates within the basal ganglia and dentate nuclei during normal aging.1 More intense iron deposition has been demonstrated within the substantia nigra in Parkinson disease, and structures affected by β amyloid plaques in Alzheimer disease, implicating iron deposition in the pathogenesis of common neurodegenerative diseases, possibly through increased oxidative stress.2,3 Direct evidence supporting a causal role for iron deposition in neurodegenerative conditions comes from a group of genetic disorders termed neurodegeneration with brain iron accumulation (NBIA), in which a variety of genetic defects in iron metabolism lead to brain iron accumulation with neuronal death in the affected brain regions.4 Four subtypes of NBIA have been defined at the molecular genetic level. Pantothenate Kinase associated neurodegeneration (PKAN, NBIA type one, MIM 234200), formerly known as Hallervorden-Spatz syndrome, is caused by mutation of the Pantothenate Kinase 2 gene (PANK2).5 Infantile neuroaxonal dystrophy (INAD, MIM 256600) is a recessive disorder with psychomotor regression due to mutations in PLA2G6.6 Mutations of the ferritin light chain gene (FTL1) cause the adult onset autosomal dominant movement disorder neuroferritinopathy (FTL, NBIA type two, hereditary ferritinopathy, MIM 606159).7 A further form of NBIA is aceruloplasminemia (aCp, MIM 604290), an autosomal recessive ceruloplasmin deficiency which results in iron deposition in the reticuloendothelial system and brain, presenting with diabetes and an extrapyramidal movement disorder in adult life.8 Extensive phenotypic overlap presents a major challenge in the clinical diagnosis of different subtypes of NBIA, particularly in the early stages. Although molecular genetic testing can provide the definitive diagnosis, comprehensive testing is only available on a research basis, and the genetic defect remains undefined in a large subgroup of patients with so-called NBIA of unknown cause. A reliable clinical investigation capable of predicting the genetic diagnosis would be useful to inform genetic counseling, predict the disease course, and ensure appropriate enrollment in clinical trials of new treatments. Dramatic evidence of focal brain iron accumulation on brain imaging is usually the first indication of NBIA, but the features distinguishing the different subtypes have yet to be defined.
