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α-Synuclein and Parkinson’s disease
Brain Research Bulletin, Vol. 50, Nos. 5/6, pp. 465– 466, 1999 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0361-9230/99/$–see front matter
PII S0361-9230(99)00136-7
␣-Synuclein and Parkinson’s disease Robert E. Burke* Departments of Neurology and Pathology, Columbia University, The College of Physicians and Surgeons, New York, NY, USA [Received 13 May 1999; Accepted 14 May 1999] within families, usually with an autosomal dominant pattern of inheritance. To their credit, it was the work of Duvoisin and his colleagues which, in spite of their own findings in the twin studies, led to the identification of a large Italian kindred from the Contursi region [1]. It was the characterization of this family which led to the mapping of a gene to chromosome 4q21-q23 [6], and ultimately to the discovery of the Ala53Thr mutation in synuclein [7]. The discovery of the mutation in synuclein had almost immediate implications for the pathogenesis of the disease, because within a few months of the report of the mutation, Spillantini and others identified ␣-synuclein in Lewy bodies [8], the proteinaceous intraneuronal inclusion which is a pathologic hallmark of the disease. The possibility that this observation may have significance for pathogenesis was supported by the original discovery of the human form of ␣-synuclein as a protein component of senile plaques of Alzheimer’s disease [9], suggesting that this protein, either in its normal or a subverted role, may participate in the formation of protein aggregates. This possibility was further supported by observations of Iwai and Saitoh [3] and Lansbury and colleagues [2] that the central, hydrophobic portion of ␣-synuclein, the non-A component (or NAC) was capable of spontaneously forming amyloid fibrils. The discovery of the ␣-synuclein mutation also strengthened the concept that there may be important overlaps in the pathogenesis of Parkinson’s, Alzheimer’s, and other neurodegenerative disease, particularly those which include Lewy body pathology. The discovery of ␣-synuclein has opened many important avenues which will need to be explored to determine its role in the pathogenesis of these diseases. Very little is known of its normal function; this will need to be determined in order to evaluate whether the mutation may lead to disease by loss of this function. It will also be important to determine whether the aggregation properties of this protein may directly relate to the formation of Lewy bodies, and whether mutations may affect aggregation. There is already some evidence that they may do so [5]. It will be important further to determine whether formation of Lewy bodies is, in fact, directly toxic to the cell, and, if so, by what mechanism. There have never been more opportunities for understanding this debilitating and enigmatic disease at a fundamental level, and the future for the application of this new knowledge to therapeutic approaches which will prevent progression has never been brighter.
As the twentieth century draws to a close, the adult-onset neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, and motor neuron disease, remain among the deepest medical enigmas. Their importance as public health problems will certainly grow as we move into the twenty-first century, and they become more prevalent as the proportion of older individuals in the population increases among advanced nations. The last 10 years or so of this century have seen a tremendous quickening of the pace in understanding some of these conditions, particularly Alzheimer’s and motor neuron disease, as specific causative mutations have been identified in some familial forms. Although our therapeutic approaches for treating Parkinson’s have led those for the other disorders, our understanding of its pathogenesis has lagged behind while molecular approaches have been so effectively applied to the others. But with the discovery in 1997 by Polymeropoulos and his colleagues of a mutation in the gene for ␣-synuclein in some families with Parkinson’s [7], our understanding of the cause of this disease has finally entered the molecular realm, and as would be expected from what has occurred in the study of the other neurodegenerative disorders, the growth of understanding is rapidly accelerating. This discovery not only created for the first time a molecular framework in which to begin to understand this disease, but also it had implications for pathogenesis, because it put Parkinson’s disease among those degenerative neurologic disorders, including Alzheimer’s, Huntington’s disease, and the other triplet repeat diseases, which may be caused by the formation of pathologic intraneuronal protein aggregates. The conceptual frameshift which this discovery produced is best understood in the context of what had been the prevailing concepts of etiology. In 1983, Langston and colleagues made the clinical observation in a group of drug addicts that illicit intravenous administration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) caused a clinical syndrome virtually identical to idiopathic Parkinson’s disease [4]. This important discovery suggested that perhaps environmental toxins resembling MPTP may cause the disease. This emphasis on the possible role of environmental factors was supported and encouraged by a study of twins, also published in 1983, which demonstrated a low concordance for Parkinson’s among monozygotic twins, not exceeding that among dizygotic twins [10]. Thus, the major concepts for the etiology of disease were oriented towards possible environmental causes for most of the 1980s and early 1990s. Nevertheless, all investigators recognized that in a small number of instances, Parkinson’s did occur
* Address for correspondence: Prof. Robert E. Burke, Departments of Neurology and Pathology, Columbia University, The College of Physicians and Surgeons, Room 308, Black Bldg, 650 W 168th St, New York, NY 10032, USA. Fax: 212-305-5450; E-mail: [email protected]
465
466
BURKE REFERENCES
1. Golbe, L. I.; Di Iorio, G.; Bonavita, V.; Miller, D. C.; Duvoisin, R. C. Autosomal dominant Parkinson’s disease. Ann. Neurol. 27:276 –282; 1990. 2. Han, H.; Weinreb, P. H.; Lansbury, P. T. J. The core Alzheimer’s peptide NAC forms amyloid fibrils which seed and are seeded by beta-amyloid: Is NAC a common trigger or target in neurodegenerative disease? Chem. Biol. 2:163–169; 1995. 3. Iwai, A.; Yoshimoto, M.; Masliah, E.; Saitoh, T. Non-A component of Alzheimer’s disease amyloid (NAC) is amyloidogenic. Biochemistry 34:10139 –10145; 1995. 4. Langston, J. W.; Ballard, P. A.; Tetrud, J. W.; Irwin, I. Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979 –980; 1983. 5. Narhi, L.; Wood, S. J.; Steavenson, S.; Jiang, Y.; Wu, G. M.; Anafi, D.; Kaufman, S. A.; Martin, F.; Sitney, K.; Denis, P.; Louis, J. C.; Wypych, J.; Biere, A. L.; Citron, M. Both familial Parkinson’s disease mutations accelerate alpha-synuclein aggregation. J. Biol. Chem. 274: 9843–9846; 1999. 6. Polymeropoulos, M. H.; Higgins, J. J.; Golbe, L. I.; Johnson, W. G.;
7.
8.
9.
10.
Ide, S. E.; Di Iorio, G.; Sanges, G.; Stenroos, E. S.; Pho, L. T.; Schaffer, A. A.; Lazzarini, A. M.; Nussbaum, R. L.; Duvoisin, R. C. Mapping of a gene for Parkinson’s disease to chromosome 4q21-q23. Science 274:1197–1199; 1996. Polymeropoulos, M. H.; Lavedan, C.; Leroy, E.; Ide, S. E.; Dehejia, A.; Dutra, A.; Pike, B.; Root, H.; Rubenstein, J.; Boyer, R.; Stenroos, E. S.; Chandrasekharappa, S.; Athanassiadou, A.; Papapetropoulos, T.; Johnson, W. G.; Lazzarini, A. M.; Duvoisin, R. C.; Golbe, L. I.; Nussbaum, R. L. Mutation in the ␣-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047; 1997. Spillantini, M. G.; Schmidt, M. L.; Lee, V. M. Y.; Trojanowski, J. Q.; Jakes, R.; Goedert, M. ␣-Synuclein in Lewy bodies. Nature 388:839 – 840; 1997. Ueda, K.; Fukushima, H.; Masliah, E.; Xia, Y.; Iwai, A.; Yoshimoto, M.; Otero, D. A. C.; Kondo, J.; Ihara, Y.; Saitoh, T. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc. Natl. Acad. Sci. USA 90:11282–11286; 1993. Ward, C. D.; Duvoisin, R. C.; Ince, S. E.; Nutt, J. D.; Eldridge, R.; Calne, D. B. Parkinson’s disease in 65 pairs of twins and in a set of quadruplets. Neurology 33:815– 824; 1983.
PII S0361-9230(99)00136-7
␣-Synuclein and Parkinson’s disease Robert E. Burke* Departments of Neurology and Pathology, Columbia University, The College of Physicians and Surgeons, New York, NY, USA [Received 13 May 1999; Accepted 14 May 1999] within families, usually with an autosomal dominant pattern of inheritance. To their credit, it was the work of Duvoisin and his colleagues which, in spite of their own findings in the twin studies, led to the identification of a large Italian kindred from the Contursi region [1]. It was the characterization of this family which led to the mapping of a gene to chromosome 4q21-q23 [6], and ultimately to the discovery of the Ala53Thr mutation in synuclein [7]. The discovery of the mutation in synuclein had almost immediate implications for the pathogenesis of the disease, because within a few months of the report of the mutation, Spillantini and others identified ␣-synuclein in Lewy bodies [8], the proteinaceous intraneuronal inclusion which is a pathologic hallmark of the disease. The possibility that this observation may have significance for pathogenesis was supported by the original discovery of the human form of ␣-synuclein as a protein component of senile plaques of Alzheimer’s disease [9], suggesting that this protein, either in its normal or a subverted role, may participate in the formation of protein aggregates. This possibility was further supported by observations of Iwai and Saitoh [3] and Lansbury and colleagues [2] that the central, hydrophobic portion of ␣-synuclein, the non-A component (or NAC) was capable of spontaneously forming amyloid fibrils. The discovery of the ␣-synuclein mutation also strengthened the concept that there may be important overlaps in the pathogenesis of Parkinson’s, Alzheimer’s, and other neurodegenerative disease, particularly those which include Lewy body pathology. The discovery of ␣-synuclein has opened many important avenues which will need to be explored to determine its role in the pathogenesis of these diseases. Very little is known of its normal function; this will need to be determined in order to evaluate whether the mutation may lead to disease by loss of this function. It will also be important to determine whether the aggregation properties of this protein may directly relate to the formation of Lewy bodies, and whether mutations may affect aggregation. There is already some evidence that they may do so [5]. It will be important further to determine whether formation of Lewy bodies is, in fact, directly toxic to the cell, and, if so, by what mechanism. There have never been more opportunities for understanding this debilitating and enigmatic disease at a fundamental level, and the future for the application of this new knowledge to therapeutic approaches which will prevent progression has never been brighter.
As the twentieth century draws to a close, the adult-onset neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, and motor neuron disease, remain among the deepest medical enigmas. Their importance as public health problems will certainly grow as we move into the twenty-first century, and they become more prevalent as the proportion of older individuals in the population increases among advanced nations. The last 10 years or so of this century have seen a tremendous quickening of the pace in understanding some of these conditions, particularly Alzheimer’s and motor neuron disease, as specific causative mutations have been identified in some familial forms. Although our therapeutic approaches for treating Parkinson’s have led those for the other disorders, our understanding of its pathogenesis has lagged behind while molecular approaches have been so effectively applied to the others. But with the discovery in 1997 by Polymeropoulos and his colleagues of a mutation in the gene for ␣-synuclein in some families with Parkinson’s [7], our understanding of the cause of this disease has finally entered the molecular realm, and as would be expected from what has occurred in the study of the other neurodegenerative disorders, the growth of understanding is rapidly accelerating. This discovery not only created for the first time a molecular framework in which to begin to understand this disease, but also it had implications for pathogenesis, because it put Parkinson’s disease among those degenerative neurologic disorders, including Alzheimer’s, Huntington’s disease, and the other triplet repeat diseases, which may be caused by the formation of pathologic intraneuronal protein aggregates. The conceptual frameshift which this discovery produced is best understood in the context of what had been the prevailing concepts of etiology. In 1983, Langston and colleagues made the clinical observation in a group of drug addicts that illicit intravenous administration of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) caused a clinical syndrome virtually identical to idiopathic Parkinson’s disease [4]. This important discovery suggested that perhaps environmental toxins resembling MPTP may cause the disease. This emphasis on the possible role of environmental factors was supported and encouraged by a study of twins, also published in 1983, which demonstrated a low concordance for Parkinson’s among monozygotic twins, not exceeding that among dizygotic twins [10]. Thus, the major concepts for the etiology of disease were oriented towards possible environmental causes for most of the 1980s and early 1990s. Nevertheless, all investigators recognized that in a small number of instances, Parkinson’s did occur
* Address for correspondence: Prof. Robert E. Burke, Departments of Neurology and Pathology, Columbia University, The College of Physicians and Surgeons, Room 308, Black Bldg, 650 W 168th St, New York, NY 10032, USA. Fax: 212-305-5450; E-mail: [email protected]
465
466
BURKE REFERENCES
1. Golbe, L. I.; Di Iorio, G.; Bonavita, V.; Miller, D. C.; Duvoisin, R. C. Autosomal dominant Parkinson’s disease. Ann. Neurol. 27:276 –282; 1990. 2. Han, H.; Weinreb, P. H.; Lansbury, P. T. J. The core Alzheimer’s peptide NAC forms amyloid fibrils which seed and are seeded by beta-amyloid: Is NAC a common trigger or target in neurodegenerative disease? Chem. Biol. 2:163–169; 1995. 3. Iwai, A.; Yoshimoto, M.; Masliah, E.; Saitoh, T. Non-A component of Alzheimer’s disease amyloid (NAC) is amyloidogenic. Biochemistry 34:10139 –10145; 1995. 4. Langston, J. W.; Ballard, P. A.; Tetrud, J. W.; Irwin, I. Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979 –980; 1983. 5. Narhi, L.; Wood, S. J.; Steavenson, S.; Jiang, Y.; Wu, G. M.; Anafi, D.; Kaufman, S. A.; Martin, F.; Sitney, K.; Denis, P.; Louis, J. C.; Wypych, J.; Biere, A. L.; Citron, M. Both familial Parkinson’s disease mutations accelerate alpha-synuclein aggregation. J. Biol. Chem. 274: 9843–9846; 1999. 6. Polymeropoulos, M. H.; Higgins, J. J.; Golbe, L. I.; Johnson, W. G.;
7.
8.
9.
10.
Ide, S. E.; Di Iorio, G.; Sanges, G.; Stenroos, E. S.; Pho, L. T.; Schaffer, A. A.; Lazzarini, A. M.; Nussbaum, R. L.; Duvoisin, R. C. Mapping of a gene for Parkinson’s disease to chromosome 4q21-q23. Science 274:1197–1199; 1996. Polymeropoulos, M. H.; Lavedan, C.; Leroy, E.; Ide, S. E.; Dehejia, A.; Dutra, A.; Pike, B.; Root, H.; Rubenstein, J.; Boyer, R.; Stenroos, E. S.; Chandrasekharappa, S.; Athanassiadou, A.; Papapetropoulos, T.; Johnson, W. G.; Lazzarini, A. M.; Duvoisin, R. C.; Golbe, L. I.; Nussbaum, R. L. Mutation in the ␣-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047; 1997. Spillantini, M. G.; Schmidt, M. L.; Lee, V. M. Y.; Trojanowski, J. Q.; Jakes, R.; Goedert, M. ␣-Synuclein in Lewy bodies. Nature 388:839 – 840; 1997. Ueda, K.; Fukushima, H.; Masliah, E.; Xia, Y.; Iwai, A.; Yoshimoto, M.; Otero, D. A. C.; Kondo, J.; Ihara, Y.; Saitoh, T. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc. Natl. Acad. Sci. USA 90:11282–11286; 1993. Ward, C. D.; Duvoisin, R. C.; Ince, S. E.; Nutt, J. D.; Eldridge, R.; Calne, D. B. Parkinson’s disease in 65 pairs of twins and in a set of quadruplets. Neurology 33:815– 824; 1983.