New Genetic Insights into Parkinson's Disease
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《新英格兰医药杂志》
Although Parkinson's disease was once considered a purely sporadic disease, recent advances in molecular genetics have revealed important genetic influences underlying the development of the disorder. Eight defined genetic loci are now associated with highly penetrant autosomal dominant or recessive Parkinson's disease (see Table).1,2 Causative mutations have been identified in five genes, and the ensuing molecular insights have led to substantial advances in our understanding of the pathogenesis of the disease and in experimental approaches to the study of the disorder.
Table. Genetic Loci Implicated in Parkinson's Disease.
The first protein implicated in familial Parkinson's disease was -synuclein, an abundant neuronal protein of unknown function. Although mutations in the gene encoding -synuclein are a very rare cause of Parkinson's disease, the identification of -synuclein mutations has been remarkably informative. Most neurodegenerative diseases are characterized by the deposition of abnormal protein aggregates. In the case of Parkinson's disease, there are aggregates found in the neuronal cell bodies that are called Lewy bodies. The description of mutations in the -synuclein gene quickly led to the discovery that -synuclein is a major protein component of Lewy bodies. The presence of Lewy bodies is an important diagnostic feature of typical Parkinson's disease, and these inclusion bodies are thus present not only in the rare patients carrying mutations in the -synuclein gene, but in patients with sporadic Parkinson's disease as well. Therefore, -synuclein may play a critical role in both genetic and sporadic forms of the disorder. The recent description of a second type of mutation affecting -synuclein lends further support to the theory that the protein is key in Parkinson's disease. The presence of an extra wild-type copy of -synuclein (triplication of the locus) also causes Parkinson's disease.
Taken together, these findings have led to a general hypothesis that the pathogenesis of Parkinson's disease involves the abnormal folding, aggregation, and deposition of -synuclein as key steps in mediating neuronal dysfunction and degeneration. Mutations in -synuclein may favor intraneuronal protein misfolding and aggregation by changing the primary amino acid sequence of the protein. The presence of an additional copy of -synuclein may also favor misfolding and aggregation of the protein, but by increasing its levels. In this model, additional, as yet undefined, genetic or epigenetic factors would increase -synuclein misfolding and aggregation in sporadic Parkinson's disease.
The identification of mutations in the gene encoding -synuclein in familial Parkinson's disease has not only led to an influential new theory of the pathogenesis of the disorder, but has also facilitated the creation of animal models of the disease in organisms as disparate as monkeys and the fruit fly drosophila. Many of these models, which are based on the expression of normal and mutant versions of human -synuclein, replicate key biochemical and cell-biologic features of Parkinson's disease. These models thus show substantial promise for furthering the understanding of pathogenesis and the development of therapies for the disorder.
Associations between two additional genes and familial Parkinson's disease also suggest that abnormalities in the clearance of proteins are important in the disease. Mutations in the gene encoding parkin, a protein with E3 ubiquitin ligase activity, cause autosomal recessive Parkinson's disease. The identification of parkin mutations in familial Parkinson's disease suggests that dysfunction of the ubiquitin–proteasome system has an important role. A major pathway for cellular protein degradation relies on a large multiprotein complex, the proteasome, that mediates the breakdown of superannuated proteins. Ubiquitin is a key component of the system, because ubiquitin is generally added to proteins by ubiquitin ligase enzymes to target them to the proteasome. The generation of free ubiquitin involves a class of proteins known as ubiquitin hydrolases. Mutations in the gene encoding one of these proteins, ubiquitin C-terminal hydrolase L1 (UCH-L1), have also been linked to familial Parkinson's disease. To date, only two patients with a mutation in UCH-L1 and Parkinson's disease have been described. However, there is also evidence that allelic variations in the gene may influence the development of Parkinson's disease, strengthening the association between UCH-L1 and the disorder.
Understandably, theories regarding the pathogenesis of Parkinson's disease have been developed independently of genetic findings. A particularly prominent model suggests that mitochondrial abnormalities leading to a failure of cellular energy production, increased levels of free radicals, or both play an important role in Parkinson's disease, and recent genetic findings now support this theory. The newest gene described in familial Parkinson's disease encodes PTEN-induced putative kinase-1 (PINK1), a mitochondrial protein kinase. Although substrates for PINK1 and a full description of its biologic function await further experimental analysis, the identification of a mitochondrial enzyme that is implicated genetically in Parkinson's disease supports the theory that mitochondrial pathology contributes to the disorder.
Mutations in the gene encoding DJ-1 have also been linked to familial Parkinson's disease. The function of DJ-1 is not known, but given its structural similarity to a bacterial stress-induced chaperone (heat shock protein 31, or Hsp31), it may assist with proper protein folding. Thus, DJ-1 mutations may be linked to abnormalities in the protein control system. Other studies have suggested that DJ-1 protects cells from oxidative damage, and mutations in DJ-1 may therefore contribute to increased levels of oxidative stress.
The identification of mutations in genes that lead to the development of Parkinson's disease with high penetrance has shown that the disorder can have a substantial genetic component. However, most cases of Parkinson's disease do not show clear familial aggregation. In these so-called sporadic cases, genetic factors that do contribute are likely to be alterations in genes that increase the risk of the disease but do not predict the development of Parkinson's disease with 100 percent accuracy. In this issue of the Journal, Aharon-Peretz and colleagues (pages 1972–1977) describe such a risk factor. They found an increase by a factor of seven in the risk of Parkinson's disease among Ashkenazi Jewish patients who carried mutations in the glucocerebrosidase gene (GBA) as compared with healthy controls. Most mutations they identified were heterozygous, although a few homozygous patients with Parkinson's disease were found as well.
Homozygous mutations in the glucocerebrosidase gene cause the glycosphingolipid-storage disorder Gaucher's disease. What might link two such seemingly disparate disorders? Recent work in both experimental animal models and in postmortem tissue samples from humans has suggested that lipids may be a critical factor influencing the toxicity of -synuclein.3 Although the precise effect of the glucocerebrosidase mutations described in Parkinson's disease on the composition of membrane lipids is unclear, the accumulation of glucocerebroside can produce an increase in the neutral phospholipid phosphatidylcholine.4 Since -synuclein exhibits relatively poor binding to neutral phospholipids, the effect of mutations in glucocerebrosidase may be to reduce the lipid binding of -synuclein and thus increase the free cytosolic -synuclein pool that is available for misfolding and aggregation.
Further work is required to determine the mechanism by which altering a single copy of the glucocerebrosidase gene influences the risk of Parkinson's disease. However, if GBA mutations do act by increasing the propensity of -synuclein to misfold and aggregate, these mutations would fit neatly into the framework suggested by genetic analysis (see Figure). In this scheme, proteins implicated genetically in the disease misfold and aggregate abnormally (-synuclein), control the ability to clear abnormal proteins (parkin, UCH-L1, and DJ-1), or determine the resistance of the cell to the stress imposed by abnormally folded and aggregated proteins (PINK1 and DJ-1).
Figure. Speculative Model of the Interactions among Proteins Implicated in Parkinson's Disease.
The binding of -synuclein to lipid membranes protects it from misfolding and aggregation. Mutations in glucocerebrosidase (GBA) alter lipid composition to favor the accumulation of cytosolic -synuclein that can then misfold and aggregate into Lewy bodies. Mutations in DJ-1 may enhance the misfolding and aggregation of -synuclein and other substrates. Mutations in parkin and UCH-L1 impair the ability of the cell to clear abnormal proteins. The misfolding and aggregation of -synuclein and possibly other proteins trigger oxidative stress and energy depletion. PINK1 mutations compromise mitochondrial function, and the response to oxidative damage relies on normal DJ-1 function.
Only additional experiments will determine whether this model of the pathways controlling neuronal toxicity in Parkinson's disease is substantially correct. However, the information provided by current and future genetic insights will doubtless continue to guide research on Parkinson's disease and promises to direct the development of rational therapies that can prevent, or at least halt the progression of, this common and devastating neurodegenerative disease.
Source Information
From the Department of Pathology, Division of Neuropathology, Brigham and Women's Hospital and Harvard Medical School, Boston.
References
Nussbaum RL, Ellis CE. Alzheimer's disease and Parkinson's disease. N Engl J Med 2003;348:1356-1364.
Vila M, Przedborski S. Genetic clues to the pathogenesis of Parkinson's disease. Nat Med 2004;10:Suppl:S58-S62.
Scherzer CR, Feany MB. Yeast genetics targets lipids in Parkinson's disease. Trends Genet 2004;20:273-277.
Wong K, Sidransky E, Verma A, et al. Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol Genet Metab 2004;82:192-207.(Mel B. Feany, M.D., Ph.D.)
Table. Genetic Loci Implicated in Parkinson's Disease.
The first protein implicated in familial Parkinson's disease was -synuclein, an abundant neuronal protein of unknown function. Although mutations in the gene encoding -synuclein are a very rare cause of Parkinson's disease, the identification of -synuclein mutations has been remarkably informative. Most neurodegenerative diseases are characterized by the deposition of abnormal protein aggregates. In the case of Parkinson's disease, there are aggregates found in the neuronal cell bodies that are called Lewy bodies. The description of mutations in the -synuclein gene quickly led to the discovery that -synuclein is a major protein component of Lewy bodies. The presence of Lewy bodies is an important diagnostic feature of typical Parkinson's disease, and these inclusion bodies are thus present not only in the rare patients carrying mutations in the -synuclein gene, but in patients with sporadic Parkinson's disease as well. Therefore, -synuclein may play a critical role in both genetic and sporadic forms of the disorder. The recent description of a second type of mutation affecting -synuclein lends further support to the theory that the protein is key in Parkinson's disease. The presence of an extra wild-type copy of -synuclein (triplication of the locus) also causes Parkinson's disease.
Taken together, these findings have led to a general hypothesis that the pathogenesis of Parkinson's disease involves the abnormal folding, aggregation, and deposition of -synuclein as key steps in mediating neuronal dysfunction and degeneration. Mutations in -synuclein may favor intraneuronal protein misfolding and aggregation by changing the primary amino acid sequence of the protein. The presence of an additional copy of -synuclein may also favor misfolding and aggregation of the protein, but by increasing its levels. In this model, additional, as yet undefined, genetic or epigenetic factors would increase -synuclein misfolding and aggregation in sporadic Parkinson's disease.
The identification of mutations in the gene encoding -synuclein in familial Parkinson's disease has not only led to an influential new theory of the pathogenesis of the disorder, but has also facilitated the creation of animal models of the disease in organisms as disparate as monkeys and the fruit fly drosophila. Many of these models, which are based on the expression of normal and mutant versions of human -synuclein, replicate key biochemical and cell-biologic features of Parkinson's disease. These models thus show substantial promise for furthering the understanding of pathogenesis and the development of therapies for the disorder.
Associations between two additional genes and familial Parkinson's disease also suggest that abnormalities in the clearance of proteins are important in the disease. Mutations in the gene encoding parkin, a protein with E3 ubiquitin ligase activity, cause autosomal recessive Parkinson's disease. The identification of parkin mutations in familial Parkinson's disease suggests that dysfunction of the ubiquitin–proteasome system has an important role. A major pathway for cellular protein degradation relies on a large multiprotein complex, the proteasome, that mediates the breakdown of superannuated proteins. Ubiquitin is a key component of the system, because ubiquitin is generally added to proteins by ubiquitin ligase enzymes to target them to the proteasome. The generation of free ubiquitin involves a class of proteins known as ubiquitin hydrolases. Mutations in the gene encoding one of these proteins, ubiquitin C-terminal hydrolase L1 (UCH-L1), have also been linked to familial Parkinson's disease. To date, only two patients with a mutation in UCH-L1 and Parkinson's disease have been described. However, there is also evidence that allelic variations in the gene may influence the development of Parkinson's disease, strengthening the association between UCH-L1 and the disorder.
Understandably, theories regarding the pathogenesis of Parkinson's disease have been developed independently of genetic findings. A particularly prominent model suggests that mitochondrial abnormalities leading to a failure of cellular energy production, increased levels of free radicals, or both play an important role in Parkinson's disease, and recent genetic findings now support this theory. The newest gene described in familial Parkinson's disease encodes PTEN-induced putative kinase-1 (PINK1), a mitochondrial protein kinase. Although substrates for PINK1 and a full description of its biologic function await further experimental analysis, the identification of a mitochondrial enzyme that is implicated genetically in Parkinson's disease supports the theory that mitochondrial pathology contributes to the disorder.
Mutations in the gene encoding DJ-1 have also been linked to familial Parkinson's disease. The function of DJ-1 is not known, but given its structural similarity to a bacterial stress-induced chaperone (heat shock protein 31, or Hsp31), it may assist with proper protein folding. Thus, DJ-1 mutations may be linked to abnormalities in the protein control system. Other studies have suggested that DJ-1 protects cells from oxidative damage, and mutations in DJ-1 may therefore contribute to increased levels of oxidative stress.
The identification of mutations in genes that lead to the development of Parkinson's disease with high penetrance has shown that the disorder can have a substantial genetic component. However, most cases of Parkinson's disease do not show clear familial aggregation. In these so-called sporadic cases, genetic factors that do contribute are likely to be alterations in genes that increase the risk of the disease but do not predict the development of Parkinson's disease with 100 percent accuracy. In this issue of the Journal, Aharon-Peretz and colleagues (pages 1972–1977) describe such a risk factor. They found an increase by a factor of seven in the risk of Parkinson's disease among Ashkenazi Jewish patients who carried mutations in the glucocerebrosidase gene (GBA) as compared with healthy controls. Most mutations they identified were heterozygous, although a few homozygous patients with Parkinson's disease were found as well.
Homozygous mutations in the glucocerebrosidase gene cause the glycosphingolipid-storage disorder Gaucher's disease. What might link two such seemingly disparate disorders? Recent work in both experimental animal models and in postmortem tissue samples from humans has suggested that lipids may be a critical factor influencing the toxicity of -synuclein.3 Although the precise effect of the glucocerebrosidase mutations described in Parkinson's disease on the composition of membrane lipids is unclear, the accumulation of glucocerebroside can produce an increase in the neutral phospholipid phosphatidylcholine.4 Since -synuclein exhibits relatively poor binding to neutral phospholipids, the effect of mutations in glucocerebrosidase may be to reduce the lipid binding of -synuclein and thus increase the free cytosolic -synuclein pool that is available for misfolding and aggregation.
Further work is required to determine the mechanism by which altering a single copy of the glucocerebrosidase gene influences the risk of Parkinson's disease. However, if GBA mutations do act by increasing the propensity of -synuclein to misfold and aggregate, these mutations would fit neatly into the framework suggested by genetic analysis (see Figure). In this scheme, proteins implicated genetically in the disease misfold and aggregate abnormally (-synuclein), control the ability to clear abnormal proteins (parkin, UCH-L1, and DJ-1), or determine the resistance of the cell to the stress imposed by abnormally folded and aggregated proteins (PINK1 and DJ-1).
Figure. Speculative Model of the Interactions among Proteins Implicated in Parkinson's Disease.
The binding of -synuclein to lipid membranes protects it from misfolding and aggregation. Mutations in glucocerebrosidase (GBA) alter lipid composition to favor the accumulation of cytosolic -synuclein that can then misfold and aggregate into Lewy bodies. Mutations in DJ-1 may enhance the misfolding and aggregation of -synuclein and other substrates. Mutations in parkin and UCH-L1 impair the ability of the cell to clear abnormal proteins. The misfolding and aggregation of -synuclein and possibly other proteins trigger oxidative stress and energy depletion. PINK1 mutations compromise mitochondrial function, and the response to oxidative damage relies on normal DJ-1 function.
Only additional experiments will determine whether this model of the pathways controlling neuronal toxicity in Parkinson's disease is substantially correct. However, the information provided by current and future genetic insights will doubtless continue to guide research on Parkinson's disease and promises to direct the development of rational therapies that can prevent, or at least halt the progression of, this common and devastating neurodegenerative disease.
Source Information
From the Department of Pathology, Division of Neuropathology, Brigham and Women's Hospital and Harvard Medical School, Boston.
References
Nussbaum RL, Ellis CE. Alzheimer's disease and Parkinson's disease. N Engl J Med 2003;348:1356-1364.
Vila M, Przedborski S. Genetic clues to the pathogenesis of Parkinson's disease. Nat Med 2004;10:Suppl:S58-S62.
Scherzer CR, Feany MB. Yeast genetics targets lipids in Parkinson's disease. Trends Genet 2004;20:273-277.
Wong K, Sidransky E, Verma A, et al. Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol Genet Metab 2004;82:192-207.(Mel B. Feany, M.D., Ph.D.)