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Robert W. Taylor - One of the best experts on this subject based on the ideXlab platform.
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The genetic basis of isolated mitochondrial Complex II Deficiency.
Molecular genetics and metabolism, 2020Co-Authors: Millie Fullerton, Robert Mcfarland, Robert W. Taylor, Charlotte L. AlstonAbstract:Abstract Mitochondrial Complex II (succinate:ubiquinone oxidoreductase) is the smallest Complex of the oxidative phosphorylation system, a tetramer of just 140 kDa. Despite its diminutive size, it is a key Complex in two coupled metabolic pathways - it oxidises succinate to fumarate in the tricarboxylic acid cycle and the electrons are used to reduce FAD to FADH2, ultimately reducing ubiquinone to ubiquinol in the respiratory chain. The biogenesis and assembly of Complex II is facilitated by four ancillary proteins, all of which are autosomally-encoded. Numerous pathogenic defects have been reported which describe two broad clinical manifestations, either susceptibility to cancer in the case of single, heterozygous germline variants, or a mitochondrial disease presentation, almost exclusively due to bi-allelic recessive variants and associated with an isolated Complex II Deficiency. Here we present a compendium of pathogenic gene variants that have been documented in the literature in patients with an isolated mitochondrial Complex II Deficiency. To date, 62 patients are described, harbouring 32 different pathogenic variants in four distinct Complex II genes: three structural subunit genes (SDHA, SDHB and SDHD) and one assembly factor gene (SDHAF1). Many pathogenic variants result in a null mutation due to nonsense, frameshift or splicing defects however, the missense variants that do occur tend to induce substitutions at highly conserved residues in regions of the proteins that are critical for binding to other subunits or substrates. There is phenotypic heterogeneity associated with defects in each Complex II gene, similar to other mitochondrial diseases.
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the genetic basis of isolated mitochondrial Complex II Deficiency
Molecular Genetics and Metabolism, 2020Co-Authors: Millie Fullerton, Robert Mcfarland, Robert W. Taylor, Charlotte L. AlstonAbstract:Abstract Mitochondrial Complex II (succinate:ubiquinone oxidoreductase) is the smallest Complex of the oxidative phosphorylation system, a tetramer of just 140 kDa. Despite its diminutive size, it is a key Complex in two coupled metabolic pathways - it oxidises succinate to fumarate in the tricarboxylic acid cycle and the electrons are used to reduce FAD to FADH2, ultimately reducing ubiquinone to ubiquinol in the respiratory chain. The biogenesis and assembly of Complex II is facilitated by four ancillary proteins, all of which are autosomally-encoded. Numerous pathogenic defects have been reported which describe two broad clinical manifestations, either susceptibility to cancer in the case of single, heterozygous germline variants, or a mitochondrial disease presentation, almost exclusively due to bi-allelic recessive variants and associated with an isolated Complex II Deficiency. Here we present a compendium of pathogenic gene variants that have been documented in the literature in patients with an isolated mitochondrial Complex II Deficiency. To date, 61 patients are described, harbouring 32 different pathogenic variants in four distinct Complex II genes: three structural subunit genes (SDHA, SDHB and SDHD) and one assembly factor gene (SDHAF1). Many pathogenic variants result in a null allele due to nonsense, frameshift or splicing defects however, the missense variants that do occur tend to induce substitutions at highly conserved residues in regions of the proteins that are critical for binding to other subunits or substrates. There is phenotypic heterogeneity associated with defects in each Complex II gene, similar to other mitochondrial diseases.
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Loss-of-function mutations in ISCA2 disrupt 4Fe-4S cluster machinery and cause a fatal leukodystrophy with hyperglycinemia and mtDNA depletion.
Human mutation, 2018Co-Authors: Joseph T. Alaimo, Robert Mcfarland, Robert W. Taylor, Charlotte L. Alston, Arnaud Besse, Ki Pang, Vivek Appadurai, Monisha Samanta, Patroula Smpokou, Penelope E. BonnenAbstract:Iron-sulfur (Fe-S) clusters are essential cofactors for proteins that participate in fundamental cellular processes including metabolism, DNA replication and repair, transcriptional regulation, and the mitochondrial electron transport chain (ETC). ISCA2 plays a role in the biogenesis of Fe-S clusters and a recent report described subjects displaying infantile-onset leukodystrophy due to bi-allelic mutation of ISCA2. We present two additional unrelated cases, and provide a more complete clinical description that includes hyperglycinemia, leukodystrophy of the brainstem with longitudinally extensive spinal cord involvement, and mtDNA Deficiency. Additionally, we characterize the role of ISCA2 in mitochondrial bioenergetics and Fe-S cluster assembly using subject cells and ISCA2 cellular knockdown models. Loss of ISCA2 diminished mitochondrial membrane potential, the mitochondrial network, basal and maximal respiration, ATP production, and activity of ETC Complexes II and IV. We specifically tested the impact of loss of ISCA2 on 2Fe-2S proteins versus 4Fe-4S proteins and observed deficits in the functioning of 4Fe-4S but not 2Fe-2S proteins. Together these data indicate loss of ISCA2 impaired function of 4Fe-4S proteins resulting in a fatal encephalopathy accompanied by a relatively unusual combination of features including mtDNA depletion alongside Complex II Deficiency and hyperglycinemia that may facilitate diagnosis of ISCA2 Deficiency patients.
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Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a Complex II gene.
Annals of neurology, 2000Co-Authors: Mark A. Birch-machin, Robert W. Taylor, Bruce Cochran, Brian A. C. Ackrell, Douglass M. TurnbullAbstract:Genetic defects affecting the mitochondrial respiratory chain are an important cause of neurological disease. Previously, we identified a family with Complex II Deficiency and late-onset neurodegenerative disease with progressive optic atrophy, ataxia, and myopathy. The affected family members are now shown to carry a C-to-T transition in one allele of the nuclear gene encoding the flavoprotein subunit of Complex II. Mutation of the equivalent base in Escherichia coli generates an inactive enzyme unable to bind flavin adenine dinucleotide covalently. Compatible with these findings, our patients have an approximate 50% decrease in Complex II and succinate dehydrogenase activity. These results suggest that genetic defects of nuclear-encoded subunits of the mitochondrial respiratory chain can result in late-onset neurodegenerative disease.
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Biochemical Investigations and Immunoblot Analyses of Two Unrelated Patients with an Isolated Deficiency in Complex II of the Mitochondrial Respiratory Chain
Biochemical and biophysical research communications, 1996Co-Authors: Mark A. Birch-machin, Robert W. Taylor, Cécile Marsac, G. Ponsot, Béatrice Parfait, Pierre Rustin, Arnold MunnichAbstract:Abstract Mitochondrial respiratory chain defects involving Complex II are comparatively rare. We report the biochemical findings in two unrelated patients who both have an isolated Complex II Deficiency (40–50% of control values). Western blot analysis of mitochondrial fractions showed different findings between the two patients. In one patient there was a decrease in the levels of both the Fp and Ip subunits whereas in the other patient the levels of all immunoreactive Complex II subunits were normal. This is the first time that an isolated Deficiency of Complex II activity associated with normal levels of protein subunits, using subunit specific antisera, has been described.
Arnold Munnich - One of the best experts on this subject based on the ideXlab platform.
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Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II Deficiency
Cell Death & Differentiation, 2010Co-Authors: E Mbaya, Bénédicte Oulès, Casper Caspersen, Rachida Tacine, Hélène Massinet, Dominique Chrétien, Arnold Munnich, Agnes Rotig, M Pennuto, Rosario RizzutoAbstract:Despite advanced knowledge on the genetic basis of oxidative phosphorylation-related diseases, the molecular and/or cellular determinants for tissue-specific dysfunction are not completely understood. Here, we report the cellular events associated with mitochondrial respiratory Complex II Deficiency occurring before cell death. Mutation or chronic inhibition of Complex II determined a large increase of basal and agonist-evoked Ca^2+ signals in the cytosol and the mitochondria, in parallel with mitochondrial dysfunction characterized by membrane potential (Δ ψ _mit) loss, [ATP] reduction and increased reactive oxygen species production. Cytosolic and mitochondrial Ca^2+ overload are linked to increased endoplasmic reticulum (ER) Ca^2+ leakage, and to SERCA2b and PMCA proteasome-dependent degradation. Increased [Ca^2+]_mit is also contributed by decreased mitochondrial motility and increased ER-mitochondria contact sites. Interestingly, increased intracellular [Ca^2+] activated on the one hand a compensatory Ca^2+-dependent glycolytic ATP production and determined on the second hand mitochondrial pathology. These results revealed the primary function for Ca^2+ signalling in the control of mitochondrial dysfunction and cellular bioenergetics outcomes linked to respiratory chain Complex II Deficiency.
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Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II Deficiency
Cell Death and Differentiation, 2010Co-Authors: Mounia Chami, Eleonore Mbaya-moutula, Bénédicte Oulès, Casper Caspersen, Rachida Tacine, Hélène Massinet, Dominique Chrétien, Arnold Munnich, Agnes Rotig, Rosario RizzutoAbstract:Despite advanced knowledge on the genetic basis of oxidative phosphorylation (OXPHOS)-related diseases, the molecular and/or cellular determinants for tissue specific dysfunction are not completely understood. Here, we report the cellular events associated with mitochondrial respiratory Complex II Deficiency occurring prior to cell death. Mutation or chronic inhibition of Complex II determined a large increase of basal and agonist-evoked Ca2+ signals in the cytosol and the mitochondria, in parallel with mitochondrial dysfunction characterized by membrane potential (∆ψmit) loss, [ATP] reduction and increased Reactive Oxygen Species (ROS) production. cytosolic and mitochondrial Ca2+ overload are linked to increased ER Ca2+ leakage, and to SERCA2b and PMCA proteasome-dependent degradation. Increased [Ca2+]mit is also contributed by decreased mitochondrial motility and increased ER-mitochondria contact sites. Interestingly, increased intracellular [Ca2+] activated on the one hand a compensatory Ca2+-dependent glycolytic ATP production and determined on the second hand mitochondrial pathology. These results revealed the primary role for Ca2+ signalling in the control of mitochondrial dysfunction and cellular bioenergetics outcomes linked to respiratory chain Complex II Deficiency.
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Biochemical Investigations and Immunoblot Analyses of Two Unrelated Patients with an Isolated Deficiency in Complex II of the Mitochondrial Respiratory Chain
Biochemical and biophysical research communications, 1996Co-Authors: Mark A. Birch-machin, Robert W. Taylor, Cécile Marsac, G. Ponsot, Béatrice Parfait, Pierre Rustin, Arnold MunnichAbstract:Abstract Mitochondrial respiratory chain defects involving Complex II are comparatively rare. We report the biochemical findings in two unrelated patients who both have an isolated Complex II Deficiency (40–50% of control values). Western blot analysis of mitochondrial fractions showed different findings between the two patients. In one patient there was a decrease in the levels of both the Fp and Ip subunits whereas in the other patient the levels of all immunoreactive Complex II subunits were normal. This is the first time that an isolated Deficiency of Complex II activity associated with normal levels of protein subunits, using subunit specific antisera, has been described.
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Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain Deficiency
Nature Genetics, 1995Co-Authors: Thomas Bourgeron, Dominique Chrétien, Arnold Munnich, Pierre Rustin, Mark Birch-machin, Marie Bourgeois, Evani Viegas-péquignot, Agnes RotigAbstract:We now report a mutation in the nuclear–encoded flavoprotein (Fp) subunit gene of the succinate dehydrogenase (SDH) in two siblings with Complex II Deficiency presenting as Leigh syndrome. Both patients were homozygous for an Arg554Trp substitution in the Fp subunit. Their parents (first cousins) were heterozygous for the mutation that occurred in a conserved domain of the protein and was absent from 120 controls. The deleterious effect of the Arg to Trp substitution on the catalytic activity of SDH was observed in a SDH ^− yeast strain transformed with mutant Fp cDNA. The Fp subunit gene is duplicated in the human genome (3q29; 5p15), with only the gene on chromosome 5 expressed in human–hamster somatic cell hybrids. This is the first report of a nuclear gene mutation causing a mitochondrial respiratory chain Deficiency in humans.
Agnes Rotig - One of the best experts on this subject based on the ideXlab platform.
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Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II Deficiency
Cell Death & Differentiation, 2010Co-Authors: E Mbaya, Bénédicte Oulès, Casper Caspersen, Rachida Tacine, Hélène Massinet, Dominique Chrétien, Arnold Munnich, Agnes Rotig, M Pennuto, Rosario RizzutoAbstract:Despite advanced knowledge on the genetic basis of oxidative phosphorylation-related diseases, the molecular and/or cellular determinants for tissue-specific dysfunction are not completely understood. Here, we report the cellular events associated with mitochondrial respiratory Complex II Deficiency occurring before cell death. Mutation or chronic inhibition of Complex II determined a large increase of basal and agonist-evoked Ca^2+ signals in the cytosol and the mitochondria, in parallel with mitochondrial dysfunction characterized by membrane potential (Δ ψ _mit) loss, [ATP] reduction and increased reactive oxygen species production. Cytosolic and mitochondrial Ca^2+ overload are linked to increased endoplasmic reticulum (ER) Ca^2+ leakage, and to SERCA2b and PMCA proteasome-dependent degradation. Increased [Ca^2+]_mit is also contributed by decreased mitochondrial motility and increased ER-mitochondria contact sites. Interestingly, increased intracellular [Ca^2+] activated on the one hand a compensatory Ca^2+-dependent glycolytic ATP production and determined on the second hand mitochondrial pathology. These results revealed the primary function for Ca^2+ signalling in the control of mitochondrial dysfunction and cellular bioenergetics outcomes linked to respiratory chain Complex II Deficiency.
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Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II Deficiency
Cell Death and Differentiation, 2010Co-Authors: Mounia Chami, Eleonore Mbaya-moutula, Bénédicte Oulès, Casper Caspersen, Rachida Tacine, Hélène Massinet, Dominique Chrétien, Arnold Munnich, Agnes Rotig, Rosario RizzutoAbstract:Despite advanced knowledge on the genetic basis of oxidative phosphorylation (OXPHOS)-related diseases, the molecular and/or cellular determinants for tissue specific dysfunction are not completely understood. Here, we report the cellular events associated with mitochondrial respiratory Complex II Deficiency occurring prior to cell death. Mutation or chronic inhibition of Complex II determined a large increase of basal and agonist-evoked Ca2+ signals in the cytosol and the mitochondria, in parallel with mitochondrial dysfunction characterized by membrane potential (∆ψmit) loss, [ATP] reduction and increased Reactive Oxygen Species (ROS) production. cytosolic and mitochondrial Ca2+ overload are linked to increased ER Ca2+ leakage, and to SERCA2b and PMCA proteasome-dependent degradation. Increased [Ca2+]mit is also contributed by decreased mitochondrial motility and increased ER-mitochondria contact sites. Interestingly, increased intracellular [Ca2+] activated on the one hand a compensatory Ca2+-dependent glycolytic ATP production and determined on the second hand mitochondrial pathology. These results revealed the primary role for Ca2+ signalling in the control of mitochondrial dysfunction and cellular bioenergetics outcomes linked to respiratory chain Complex II Deficiency.
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Mutation of a nuclear succinate dehydrogenase gene results in mitochondrial respiratory chain Deficiency
Nature Genetics, 1995Co-Authors: Thomas Bourgeron, Dominique Chrétien, Arnold Munnich, Pierre Rustin, Mark Birch-machin, Marie Bourgeois, Evani Viegas-péquignot, Agnes RotigAbstract:We now report a mutation in the nuclear–encoded flavoprotein (Fp) subunit gene of the succinate dehydrogenase (SDH) in two siblings with Complex II Deficiency presenting as Leigh syndrome. Both patients were homozygous for an Arg554Trp substitution in the Fp subunit. Their parents (first cousins) were heterozygous for the mutation that occurred in a conserved domain of the protein and was absent from 120 controls. The deleterious effect of the Arg to Trp substitution on the catalytic activity of SDH was observed in a SDH ^− yeast strain transformed with mutant Fp cDNA. The Fp subunit gene is duplicated in the human genome (3q29; 5p15), with only the gene on chromosome 5 expressed in human–hamster somatic cell hybrids. This is the first report of a nuclear gene mutation causing a mitochondrial respiratory chain Deficiency in humans.
Rosario Rizzuto - One of the best experts on this subject based on the ideXlab platform.
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Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II Deficiency
Cell Death & Differentiation, 2010Co-Authors: E Mbaya, Bénédicte Oulès, Casper Caspersen, Rachida Tacine, Hélène Massinet, Dominique Chrétien, Arnold Munnich, Agnes Rotig, M Pennuto, Rosario RizzutoAbstract:Despite advanced knowledge on the genetic basis of oxidative phosphorylation-related diseases, the molecular and/or cellular determinants for tissue-specific dysfunction are not completely understood. Here, we report the cellular events associated with mitochondrial respiratory Complex II Deficiency occurring before cell death. Mutation or chronic inhibition of Complex II determined a large increase of basal and agonist-evoked Ca^2+ signals in the cytosol and the mitochondria, in parallel with mitochondrial dysfunction characterized by membrane potential (Δ ψ _mit) loss, [ATP] reduction and increased reactive oxygen species production. Cytosolic and mitochondrial Ca^2+ overload are linked to increased endoplasmic reticulum (ER) Ca^2+ leakage, and to SERCA2b and PMCA proteasome-dependent degradation. Increased [Ca^2+]_mit is also contributed by decreased mitochondrial motility and increased ER-mitochondria contact sites. Interestingly, increased intracellular [Ca^2+] activated on the one hand a compensatory Ca^2+-dependent glycolytic ATP production and determined on the second hand mitochondrial pathology. These results revealed the primary function for Ca^2+ signalling in the control of mitochondrial dysfunction and cellular bioenergetics outcomes linked to respiratory chain Complex II Deficiency.
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Calcium signalling-dependent mitochondrial dysfunction and bioenergetics regulation in respiratory chain Complex II Deficiency
Cell Death and Differentiation, 2010Co-Authors: Mounia Chami, Eleonore Mbaya-moutula, Bénédicte Oulès, Casper Caspersen, Rachida Tacine, Hélène Massinet, Dominique Chrétien, Arnold Munnich, Agnes Rotig, Rosario RizzutoAbstract:Despite advanced knowledge on the genetic basis of oxidative phosphorylation (OXPHOS)-related diseases, the molecular and/or cellular determinants for tissue specific dysfunction are not completely understood. Here, we report the cellular events associated with mitochondrial respiratory Complex II Deficiency occurring prior to cell death. Mutation or chronic inhibition of Complex II determined a large increase of basal and agonist-evoked Ca2+ signals in the cytosol and the mitochondria, in parallel with mitochondrial dysfunction characterized by membrane potential (∆ψmit) loss, [ATP] reduction and increased Reactive Oxygen Species (ROS) production. cytosolic and mitochondrial Ca2+ overload are linked to increased ER Ca2+ leakage, and to SERCA2b and PMCA proteasome-dependent degradation. Increased [Ca2+]mit is also contributed by decreased mitochondrial motility and increased ER-mitochondria contact sites. Interestingly, increased intracellular [Ca2+] activated on the one hand a compensatory Ca2+-dependent glycolytic ATP production and determined on the second hand mitochondrial pathology. These results revealed the primary role for Ca2+ signalling in the control of mitochondrial dysfunction and cellular bioenergetics outcomes linked to respiratory chain Complex II Deficiency.
Brian A. C. Ackrell - One of the best experts on this subject based on the ideXlab platform.
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Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a Complex II gene.
Annals of neurology, 2000Co-Authors: Mark A. Birch-machin, Robert W. Taylor, Bruce Cochran, Brian A. C. Ackrell, Douglass M. TurnbullAbstract:Genetic defects affecting the mitochondrial respiratory chain are an important cause of neurological disease. Previously, we identified a family with Complex II Deficiency and late-onset neurodegenerative disease with progressive optic atrophy, ataxia, and myopathy. The affected family members are now shown to carry a C-to-T transition in one allele of the nuclear gene encoding the flavoprotein subunit of Complex II. Mutation of the equivalent base in Escherichia coli generates an inactive enzyme unable to bind flavin adenine dinucleotide covalently. Compatible with these findings, our patients have an approximate 50% decrease in Complex II and succinate dehydrogenase activity. These results suggest that genetic defects of nuclear-encoded subunits of the mitochondrial respiratory chain can result in late-onset neurodegenerative disease.
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Deficiency of Complex II of the mitochondrial respiratory chain in late onset optic atrophy and ataxia
Annals of Neurology, 1996Co-Authors: Robert W. Taylor, Bruce Cochran, Brian A. C. Ackrell, J. Schaefer, Louise Taylor, Raad Shakir, Laurence A. Bindoff, Margaret J. Jackson, Mark A Birchmachin, Philip G. GriffithsAbstract:Defects of the mitochondrial respiratory chain are increasingly being recognized as an important cause of neurological disease in humans. In many of these patients, the biochemical defect results from an abnormality of the mitochondrial genome. Respiratory chain defects involving Complex II, which is entirely encoded by the nuclear genome, are comparatively rare. We report the clinical and biochemical findings in 2 elderly sisters who presented with late-onset neurodegenerative disease. In both patients, a partial Deficiency of Complex II (approximately 50% of control values) was shown to be present in mitochondria from muscle and platelets. The enzyme defect was not expressed in cultured skin fibroblasts or immortalized lymphocytes. There was an overexpression of the 70-kd flavoprotein subunit in muscle mitochondria from both patients, although we showed that this subunit is present in normal amounts in mitochondrial membranes. Our studies highlight the diversity of the clinical presentation of respiratory chain disease and that Complex II Deficiency should enter the differential diagnosis of certain patients with late-onset neurodegenerative disease.
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Deficiency of Complex II of the mitochondrial respiratory chain in late‐onset optic atrophy and ataxia
Annals of neurology, 1996Co-Authors: Robert W. Taylor, Mark A. Birch-machin, Bruce Cochran, Brian A. C. Ackrell, J. Schaefer, Louise Taylor, Raad Shakir, Laurence A. Bindoff, Margaret J. Jackson, Philip G. GriffithsAbstract:Defects of the mitochondrial respiratory chain are increasingly being recognized as an important cause of neurological disease in humans. In many of these patients, the biochemical defect results from an abnormality of the mitochondrial genome. Respiratory chain defects involving Complex II, which is entirely encoded by the nuclear genome, are comparatively rare. We report the clinical and biochemical findings in 2 elderly sisters who presented with late-onset neurodegenerative disease. In both patients, a partial Deficiency of Complex II (approximately 50% of control values) was shown to be present in mitochondria from muscle and platelets. The enzyme defect was not expressed in cultured skin fibroblasts or immortalized lymphocytes. There was an overexpression of the 70-kd flavoprotein subunit in muscle mitochondria from both patients, although we showed that this subunit is present in normal amounts in mitochondrial membranes. Our studies highlight the diversity of the clinical presentation of respiratory chain disease and that Complex II Deficiency should enter the differential diagnosis of certain patients with late-onset neurodegenerative disease.
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Deficiencies of NADH and succinate dehydrogenases in degenerative diseases and myopathies
Biochimica et biophysica acta, 1995Co-Authors: Thomas P. Singer, Rona R. Ramsay, Brian A. C. AckrellAbstract:This paper examines the experimental foundations of reports in the literature on mitochondrial diseases involving Complexes I and II of the respiratory chain. Many of the reports may be questioned on the basis of the assay conditions used which disregard established knowledge of the precautions required for valid activity measurements. In addition, some findings are open to question because of the experimental material chosen for the study, such as the measurement of NADH oxidase activity in platelets in Parkinson's disease, which affects selectively the dopamine neurons, or the use of autopsy material stored for prolonged periods during which post-mortem changes may have occurred. Deficiencies claimed to involve several components of the respiratory chain may reflect indirect effects, such as defects in the synthesis of iron-sulfur clusters or in the availability of iron, rather than mutations in the genes coding for the deficient enzymes. Nevertheless, there are a few instances reported of Complex II Deficiency free from such criticisms. As to Complex I, idiopathic Parkinsonism appears to involve a documentable decline in the activity of this enzyme. Using the model system provided by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces biochemical, pharmacological, and clinical syndromes closely resembling Parkinsonism, the etiology of the disease is examined.