Skip to main content
×
Home
    • Aa
    • Aa

Molecular pathogenesis of Parkinson disease: insights from genetic studies

  • Thomas Gasser (a1)
Abstract

Over the past few years, genetic findings have changed our views on the molecular pathogenesis of Parkinson disease (PD), as mutations in a growing number of genes have been found to cause monogenic forms of the disorder. These mutations cause neuronal dysfunction and neurodegeneration either by a toxic gain of function, as in the case of the dominant forms of monogenic PD caused by mutations in the genes for α-synuclein or LRRK2, or by a loss of an intrinsic protective function, as is likely for the recessive PD genes parkin (PRKN), PINK1 and DJ-1. Evidence is emerging that at least some of the pathways uncovered in the rare monogenic forms of PD may play a direct role in the aetiology of the common sporadic disorder and that variants of the respective genes contribute to the risk of developing the disease. These findings will allow the search for new treatment strategies that focus on the underlying molecular pathophysiology, rather than simply on ameliorating symptoms.

Copyright
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

1 W. Poewe (2009) Treatments for Parkinson disease–past achievements and current clinical needs. Neurology 72, S65-73

3 T. Gasser (2007) Update on the genetics of Parkinson's disease. Movement Disorders 22 (Suppl 17), S343-350

4 M.J. Farrer (2007) Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia. Parkinsonism & Related Disorders 13, 89-92

5 M.H. Polymeropoulos (1997) Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045-2047

6 R. Krüger (1998) Ala30Pro mutation in the gene encoding a-synuclein in Parkinson's disease. Nature Genetics 18, 106-108

7 J.J. Zarranz (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Annals of Neurology 55, 164-173

8 D. Berg (2005) Alpha-synuclein and Parkinson's disease: implications from the screening of more than 1,900 patients. Movement Disorders 20, 1191-1194

9 L.I. Golbe (1996) Clinical genetic analysis of Parkinson's disease in the Contursi kindred. Annals of Neurology 40, 767-775

10 J.E. Duda (2002) Concurrence of alpha-synuclein and tau brain pathology in the Contursi kindred. Acta Neuropathologica 104, 7-11

11 M.G. Spillantini (1997) Alpha-synuclein in Lewy bodies. Nature 388, 839-840

12 M. Goedert , M.G. Spillantini and S.W. Davies (1998) Filamentous nerve cell inclusions in neurodegenerative diseases. Current Opinion in Neurobiology 8, 619-632

13 M.R. Cookson and M. van der Brug (2007) Cell systems and the toxic mechanism(s) of alpha-synuclein. Experimental Neurology 209, 5-11

14 A.B. Singleton (2003) alpha-Synuclein locus triplication causes Parkinson's disease. Science 302, 841

15 P. Ibanez (2004) Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease. Lancet 364, 1169-1171

16 D.W. Miller (2004) Alpha-synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication. Neurology 62, 1835-1838

17 M.C. Chartier-Harlin (2004) Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364, 1167-1169

18 P.H. Jensen (1998) Binding of alpha-synuclein to brain vesicles is abolished by familial Parkinson's disease mutation. Journal of Biological Chemistry 273, 26292-26294

19 A. Abeliovich (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25, 239-252

21 E. Masliah (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287, 1265-1269

23 M.B. Feany and W.W. Bender (2000) A Drosophila model of Parkinson's disease. Nature 404, 394-398

24 J.C. Greene (2003) Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proceedings of the National Academy of Sciences of the United States of America 100, 4078-4083

25 P.K. Auluck (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295, 865-868

26 M. Funayama (2002) A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Annals of Neurology 51, 296-301

27 A. Zimprich (2004) Mutations in LRRK2 cause autosomal-dominant Parkinsonism with pleomorphic pathology. Neuron 44, 601-607

28 C. Paisan-Ruiz (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 44, 595-600

29 A. Di Fonzo (2006) Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease. European Journal of Human Genetics 14, 322-331

31 W.C. Nichols (2005) Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease. Lancet 365, 410-412

32 A. Di Fonzo (2005) A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet 365, 412-415

33 J. Kachergus (2005) Identification of a novel LRRK2 mutation linked to autosomal dominant Parkinsonism: evidence of a common founder across European populations. American Journal of Human Genetics 76, 672-680

34 W.P. Gilks (2005) A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 365, 415-416

35 L.J. Ozelius (2006) LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. New England Journal of Medicine 354, 424-425

36 S. Lesage (2006) LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. New England Journal of Medicine 354, 422-423

37 S. Goldwurm (2007) Evaluation of LRRK2 G2019S penetrance: relevance for genetic counseling in Parkinson disease. Neurology 68, 1141-1143

38 A. Di Fonzo (2006) A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan. Neurogenetics 7, 133-138

39 E.K. Tan (2007) The LRRK2 Gly2385Arg variant is associated with Parkinson's disease: genetic and functional evidence. Human Genetics 120, 857-863

40 M. Funayama (2007) Leucine-rich repeat kinase 2 G2385R variant is a risk factor for Parkinson disease in Asian population. Neuroreport 18, 273-275

41 C.J. Gloeckner (2006) The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Human Molecular Genetics 15, 223-232

42 E. Greggio (2007) Mutations in LRRK2/dardarin associated with Parkinson disease are more toxic than equivalent mutations in the homologous kinase LRRK1. Journal of Neurochemistry 102, 93-102

43 I.F. Mata (2005) Lrrk2 pathogenic substitutions in Parkinson's disease. Neurogenetics 6, 171-177

44 J.M. Bras (2005) G2019s dardarin substitution is a common cause of Parkinson's disease in a Portuguese cohort. Movement Disorders 20, 1653-1655

45 D.G. Healy (2008) Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurology 7, 583-590

46 J.C. Dachsel (2006) Digenic parkinsonism: investigation of the synergistic effects of PRKN and LRRK2. Neuroscience Letters 410, 80-84

47 L. Bosgraaf and P.J. Van Haastert (2003) Roc, a Ras/GTPase domain in complex proteins. Biochimica et Biophysica Acta 1643, 5-10

48 W.W. Smith (2005) Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proceedings of the National Academy of Sciences of the United States of America 102, 18676-18681

49 A.B. West (2007) Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Human Molecular Genetics 16, 223-232

50 E. Greggio (2006) Kinase activity is required for the toxic effects of mutant LRRK2/dardarin. Neurobiology of Disease 23, 329-341

51 O.A. Ross (2006) Lrrk2 and Lewy body disease. Annals of Neurology 59, 388-393

52 J.C. Dachsel (2007) Lrrk2 G2019S substitution in frontotemporal lobar degeneration with ubiquitin-immunoreactive neuronal inclusions. Acta Neuropathologica 113, 601-606

53 J. Aharon-Peretz , H. Rosenbaum and R. Gershoni-Baruch (2004) Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. New England Journal of Medicine 351, 1972-1977

54 I.F. Mata (2008) Glucocerebrosidase gene mutations: a risk factor for Lewy body disorders. Archives of Neurology 65, 379-382

55 E.V. De Marco (2008) Glucocerebrosidase gene mutations are associated with Parkinson's disease in southern Italy. Movement Disorders 23, 460-463

56 S.G. Ziegler (2007) Glucocerebrosidase mutations in Chinese subjects from Taiwan with sporadic Parkinson disease. Molecular Genetics and Metabolism 91, 195-200

57 O. Goker-Alpan (2006) Glucocerebrosidase mutations are an important risk factor for Lewy body disorders. Neurology 67, 908-910

58 A. Ishikawa and S. Tsuji (1996) Clinical analysis of 17 patients in 12 Japanese families with autosomal-recessive type juvenile parkinsonism. Neurology 47, 160-166

59 H. Ichinose (1994) Hereditary progressive dystonia with marked diurnal fluctuation caused by mutations in the GTP cyclohydrolase I gene. Nature Genetics 8, 236-242

62 N. Hattori (1998) Molecular genetic analysis of a novel Parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the Parkin gene in affected individuals. Annals of Neurology 44, 935-941

63 C.B. Lücking (1998) Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism. The European Consortium on Genetic Susceptibility in Parkinson's Disease and the French Parkinson's Disease Genetics Study Group. Lancet 352, 1355-1356

64 N. Abbas (1999) A wide variety of mutations in the parkin gene are responsible for autosomal recessive parkinsonism in Europe. Human Molecular Genetics 8, 567-574

65 C.B. Lücking (2000) Association between Early-Onset Parkinson's Disease and Mutations in the Parkin Gene. New England Journal of Medicine 342, 1560-1567

66 K. Hedrich (2004) Distribution, type, and origin of Parkin mutations: review and case studies. Movement Disorders 19, 1146-1157

67 C.B. Lücking (2001) Pseudo-dominant inheritance and exon 2 triplication in a family with parkin gene mutations. Neurology 57, 924-927

68 M. Periquet (2003) Parkin mutations are frequent in patients with isolated early-onset parkinsonism. Brain 126, 1271-1278

69 M. Periquet (2001) Origin of the Mutations in the parkin Gene in Europe: Exon Rearrangements Are Independent Recurrent Events, whereas Point Mutations May Result from Founder Effects. American Journal of Human Genetics 68, 617-626

70 C. Klein (2000) Parkin deletions in a family with adult-onset, tremor-dominant parkinsonism: expanding the phenotype. Annals of Neurology 48, 65-71

71 E.M. Valente (2004) Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158-1160

72 E.M. Valente (2004) PINK1 mutations are associated with sporadic early-onset parkinsonism. Annals of Neurology 56, 336-341

73 Y. Hatano (2004) Novel PINK1 mutations in early-onset parkinsonism. Annals of Neurology 56, 424-427

74 V. Bonifati (2005) Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes. Neurology 65, 87-95

75 K. Hedrich (2006) Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit? Archives of Neurology 63, 833-838

76 J. Prestel (2008) Clinical and molecular characterisation of a Parkinson family with a novel PINK1 mutation. Journal of Neurology 255, 643-648

77 R. Marongiu (2007) Whole gene deletion and splicing mutations expand the PINK1 genotypic spectrum. Human Mutation 28, 98

78 A. Albanese (2005) The PINK1 phenotype can be indistinguishable from idiopathic Parkinson disease. Neurology 64 1958-1960

79 L. Ephraty (2007) Neuropsychiatric and cognitive features in autosomal-recessive early parkinsonism due to PINK1 mutations. Movement Disorders 22, 566-569

80 C.M. van Duijn (2001) Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36. American Journal of Human Genetics 69, 629-634

81 V. Bonifati (2002) Mutations in the DJ-1 gene associated with autosomal recessive early-onset Parkinsonism. Science 299, 256-259

82 P.M. Abou-Sleiman (2003) The role of pathogenic DJ-1 mutations in Parkinson's disease. Annals of Neurology 54, 283-286

83 R. Hering (2004) Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7). Human Mutation 24, 321-329

84 G. Annesi (2005) DJ-1 mutations and parkinsonism-dementia-amyotrophic lateral sclerosis complex. Annals of Neurology 58, 803-807

85 H. Takahashi (1994) Familial juvenile parkinsonism: clinical and pathologic study in a family. Neurology 44, 437-441

86 B.P. van De Warrenburg (2001) Clinical and pathologic abnormalities in a family with parkinsonism and parkin gene mutations. Neurology 56, 555-557

87 H. Mori (1998) Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q. Neurology 51, 890-892

88 M. Farrer (2001) Lewy bodies and parkinsonism in families with parkin mutations. Annals of Neurology 50, 293-300

89 P.P. Pramstaller (2005) Lewy body Parkinson's disease in a large pedigree with 77 Parkin mutation carriers. Annals of Neurology 58, 411-422

91 K.K. Chung (2001) Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nature Medicine 7, 1144-1150

92 Y. Imai (2001) An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105, 891-902

93 Y. Zhang (2000) Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proceedings of the National Academy of Sciences of the United States of America 97, 13354-13359

94 M. Joch (2007) Parkin-mediated monoubiquitination of the PDZ protein PICK1 regulates the activity of acid-sensing ion channels. Molecular Biology of the Cell 18, 3105-3118

95 A.H. Schapira (2008) Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurology 7, 97-109

96 Y. Kuroda (2006) Parkin enhances mitochondrial biogenesis in proliferating cells. Human Molecular Genetics 15, 883-895

97 J.J. Palacino (2004) Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. Journal of Biological Chemistry 279, 18614-18622

98 C.C. Stichel (2007) Mono- and double-mutant mouse models of Parkinson's disease display severe mitochondrial damage. Human Molecular Genetics 16, 2377-2393

99 Y. Yang (2006) Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proceedings of the National Academy of Sciences of the United States of America 103, 10793-10798

100 H. Mortiboys (2008) Mitochondrial function and morphology are impaired in parkin-mutant fibroblasts. Annals of Neurology 64, 555-565

101 H.H. Hoepken (2007) Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6. Neurobiology of Disease 25, 401-411

102 A.C. Poole (2008) The PINK1/Parkin pathway regulates mitochondrial morphology. Proceedings of the National Academy of Sciences of the United States of America 105, 1638-1643

103 N. Lev (2006) Role of DJ-1 in Parkinson's disease. Journal of Molecular Neuroscience 29, 215-225

104 R.M. Canet-Aviles (2004) The Parkinson's disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proceedings of the National Academy of Sciences of the United States of America 101, 9103-9108

105 H. Xiong (2009) Parkin, PINK1, and DJ-1 form a ubiquitin E3 ligase complex promoting unfolded protein degradation. Journal of Clinical Investigation 119, 650-660

106 A.S. Najim al Din (1994) Pallido-pyramidal degeneration, supranuclear upgaze paresis and dementia: Kufor-Rakeb syndrome. Acta Neurologica Scandinavica 89, 347-352

107 A. Ramirez (2006) Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nature Genetics 38, 1184-1191

108 C. Vilarino-Guell (2009) ATP13A2 variability in Parkinson disease. Human Mutation 30, 406-410

109 N.V. Morgan (2006) PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nature Genetics 38, 752-754

110 C. Paisan-Ruiz (2009) Characterization of PLA2G6 as a locus for dystonia-parkinsonism. Annals of Neurology 65, 19-23

111 A. Di Fonzo (2009) FBXO7 mutations cause autosomal recessive, early-onset parkinsonian-pyramidal syndrome. Neurology 72, 240-245

112 T. Gasser (1998) A susceptibility locus for Parkinson's disease maps to chromosome 2p13. Nature Genetics 18, 262-265

113 A.L. DeStefano (2002) PARK3 influences age at onset in Parkinson disease: a genome scan in the GenePD study. American Journal of Human Genetics 70, 1089-1095

114 N. Pankratz (2004) Genes influencing Parkinson disease onset: replication of PARK3 and identification of novel loci. Neurology 62, 1616-1618

115 S. Karamohamed (2003) A haplotype at the PARK3 locus influences onset age for Parkinson's disease: the GenePD study. Neurology 61, 1557-1561

116 M. Sharma (2006) The sepiapterin reductase gene region reveals association in the PARK3 locus: analysis of familial and sporadic Parkinson's disease in European populations. Journal of Medical Genetics 43, 557-562

117 E. Leroy (1998) The ubiquitin pathway in Parkinson's disease. Nature 395, 451-452

118 D.M. Maraganore (2004) UCHL1 is a Parkinson's disease susceptibility gene. Annals of Neurology 55, 512-521

119 A.A. Hicks (2002) A susceptibility gene for late-onset idiopathic Parkinson's disease. Annals of Neurology 52, 549-555

120 N. Pankratz (2003) Significant linkage of Parkinson disease to chromosome 2q36-37. American Journal of Human Genetics 72, 1053-1057

121 J. Prestel (2005) PARK11 is not linked with Parkinson's disease in European families. European Journal of Human Genetics 13, 193-197

122 C. Lautier (2008) Mutations in the GIGYF2 (TNRC15) gene at the PARK11 locus in familial Parkinson disease. American Journal of Human Genetics 82, 822-833

123 J. Bras (2008) Lack of replication of association between GIGYF2 variants and Parkinson disease. Human Molecular Genetics 18, 341-346

124 W.C. Nichols (2009) Variation in GIGYF2 is not associated with Parkinson disease. Neurology 72, 1886-92

126 K.M. Strauss (2005) Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Human Molecular Genetics 14, 2099-2111

127 D.M. Maraganore (2006) Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease. JAMA: the Journal of the American Medical Association 296, 661-670

128 J.C. Mueller (2005) Multiple regions of alpha-synuclein are associated with Parkinson's disease. Annals of Neurology 57, 535-541

129 I. Mizuta (2006) Multiple candidate gene analysis identifies {alpha}-synuclein as a susceptibility gene for sporadic Parkinson's disease. Human Molecular Genetics 15, 1151-1158

130 A. Goris (2007) Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson's disease. Annals of Neurology 62, 145-153

131 S. Winkler (2007) alpha-Synuclein and Parkinson disease susceptibility. Neurology 69, 1745-1750

132 O.A. Ross (2007) Familial genes in sporadic disease: common variants of alpha-synuclein gene associate with Parkinson's disease. Mechanisms of Ageing and Development 128, 378-382

133 R. Myhre (2008) Multiple alpha-synuclein gene polymorphisms are associated with Parkinson's disease in a Norwegian population. Acta Neurologica Scandinavica 118, 320-327

134 N. Pankratz (2009) Genomewide association study for susceptibility genes contributing to familial Parkinson disease. Human Genetics 124, 593-605

135 J. Fuchs (2008) Genetic variability in the SNCA gene influences alpha-synuclein levels in the blood and brain. FASEB Journal 22, 1327-1334

136 D.G. Healy (2004) Tau gene and Parkinson's disease: a case-control study and meta-analysis. Journal of Neurology Neurosurgery and Psychiatry 75, 962-965

137 E.R. Martin (2001) Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease. JAMA: the Journal of the American Medical Association 286, 2245-2250

138 L. Skipper (2004) Linkage disequilibrium and association of MAPT H1 in Parkinson disease. American Journal of Human Genetics 75, 669-677

139 R. de Silva (2002) The tau locus is not significantly associated with pathologically confirmed sporadic Parkinson's disease. Neuroscience Letters 330, 201-203

140 G.K. Wenning and K.A. Jellinger (2005) The role of alpha-synuclein and tau in neurodegenerative movement disorders. Current Opinion in Neurology 18, 357-362

141 K. Arima (1999) Cellular co-localization of phosphorylated tau- and NACP/alpha- synuclein-epitopes in lewy bodies in sporadic Parkinson's disease and in dementia with lewy bodies. Brain Research 843, 53-61

142 W.R. Galpern and A.E. Lang (2006) Interface between tauopathies and synucleinopathies: a tale of two proteins. Annals of Neurology 59, 449-458

143 N.L. Khan (2002) Progression of nigrostriatal dysfunction in a parkin kindred: an [18F]dopa PET and clinical study. Brain 125, 2248-2256

144 R. Hilker (2001) Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial parkinsonism associated with mutations in the parkin gene. Annals of Neurology 49, 367-376

145 P.P. Pramstaller (2002) Phenotypic variability in a large kindred (Family LA) with deletions in the parkin gene. Movement Disorders 17, 424-426

146 S.J. Lincoln (2003) Parkin variants in North American Parkinson's disease: cases and controls. Movement Disorders 18, 1306-1311

147 D.M. Kay (2007) Heterozygous parkin point mutations are as common in control subjects as in Parkinson's patients. Annals of Neurology 61, 47-54

148 O. Chiba-Falek (2005) Regulation of alpha-synuclein expression by poly (ADP ribose) polymerase-1 (PARP-1) binding to the NACP-Rep1 polymorphic site upstream of the SNCA gene. American Journal of Human Genetics 76, 478-492

149 S. Higashi (2007) Localization of Parkinson's disease-associated LRRK2 in normal and pathological human brain. Brain Research 1155, 208-219

A. Gupta , V.L. Dawson and T.M. Dawson (2008) What causes cell death in Parkinson's disease? Annals of Neurology 64 Suppl 2, S3-15

J. Hardy (2005) Expression of normal sequence pathogenic proteins for neurodegenerative disease contributes to disease risk: ‘permissive templating’ as a general mechanism underlying neurodegeneration. Biochemical Society Transactions 33, 578-581

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Expert Reviews in Molecular Medicine
  • ISSN: -
  • EISSN: 1462-3994
  • URL: /core/journals/expert-reviews-in-molecular-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Metrics

Full text views

Total number of HTML views: 8
Total number of PDF views: 58 *
Loading metrics...

Abstract views

Total abstract views: 275 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 24th March 2017. This data will be updated every 24 hours.