Disorders with Synuclein Pathology and Parkinsonism

Laura L Kilarski, Cardiff University, Cardiff, UK
Vladimir L Buchman, Cardiff University, Cardiff, UK
Huw R Morris, Cardiff University, Cardiff, UK

Published online: March 2009

DOI: 10.1002/9780470015902.a0006031

A variety of neurodegenerative disorders are classified as synucleinopathies based on the presence of prominent -synuclein pathology. These diseases include Parkinson disease (PD) and dementia with Lewy bodies (with neuronal Lewy body formation) and multiple system atrophy (with glial cytoplasmic inclusions). The normal function of -synuclein includes regulation of pre-synaptic vesicles. Autosomal dominant PD can be due to coding mutations or multiplications of the -synuclein gene (SNCA). The coding mutations are thought to lead to a gain of function, in particular acceleration of the formation of proto-fibrils. Duplications and triplications of SNCA lead to autosomal dominant PD with a gene dosage effect on age of onset and clinical severity; variants in the SNCA promoter which lead to an upregulation of SNCA expression are associated with an increased risk of sporadic PD.

Key concepts

  • hyphen;Synuclein is deposited in the common neurodegenerative conditions Parkinson disease (PD), and dementia with Lewy bodies as neuronal cytoplasmic inclusions (Lewy bodies).
  • The normal function of hyphen;synuclein is incompletely understood but is likely to involve interaction with, and regulation of synaptic vesicles.
  • There is some evidence that hyphen;synuclein may have a role as a cellular chaperone and in interacting with the proteasome.
  • Mendelian coding mutations in the hyphen;synuclein gene (SNCA) can lead to autosomal dominant PD and dementia with Lewy bodies (DLB).
  • SNCA mutations lead to an enhancement of protofibril formation as well as affecting normal hyphen;synuclein function.
  • SNCA duplications and triplications lead to autosomal dominant PD: an increase in the transcription of normal sequence SNCA can lead to disease.
  • Promoter variation at the SNCA is associated with PD; in vitro evidence suggests that protective promoter alleles lead to a downregulation of SNCA expression.

Keywords: -synuclein; Parkinson disease; multiple system atrophy; Lewy body; dementia with Lewy bodies

Figure 1. Structure of -synuclein showing the location of the Mendelian coding mutations. Kindly provided by Dr Morris.
close
 References
    Abeliovich A, Schmitz Y, Farina I et al. (2000) Mice lacking -synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25: 239–252.
    Beyer K (2006) -Synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers. Acta Neuropathologica 112: 237–251.
    Bonifati V (2008) Recent advances in the genetics of dementia with lewy bodies. Current Neurology and Neuroscience Reports 8: 187–189.
    Cabin DE, Shimazu K, Murphy D et al. (2002) Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking -synuclein. Journal of Neuroscience 22: 8797–8807.
    Chandra S, Gallardo G, Fernández-Chacón R, Schlüter O and Südhof T (2005) -Synuclein cooperates with CSP in preventing neurodegeneration. Cell 123: 383–396.
    Chiba-Falek O and Nussbaum RL (2003) Regulation of -synuclein expression: implications for Parkinson's disease. Cold Spring Harbor Symposia on Quantitative Biology 68: 409–415.
    Choi W, Zibaee S, Jakes R et al. (2004) Mutation E46K increases phospholipid binding and assembly into filaments of human -synuclein. FEBS Letters 576: 363–368.
    Clayton DF and George JM (1998) The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends in Neurosciences 21: 249–254.
    Drolet RE, Behrouz B, Lookingland KJ and Goudreau JL (2004) Mice lacking -synuclein have an attenuated loss of striatal dopamine following prolonged chronic MPTP administration. Neurotoxicology 25: 761–769.
    Farrer M, Kachergus J, Forno L et al. (2004) Comparison of kindreds with Parkinsonism and -synuclein genomic multiplications. Annals of Neurology 55: 174–179.
    Fuchs J, Tichopad A, Golub Y et al. (2008) Genetic variability in the SNCA gene influences -synuclein levels in the blood and brain. The FASEB Journal 22: 1327–1334.
    Galvin JE, Giasson B, Hurtig HI, Lee VMY and Trojanowski JQ (2000) Neurodegeneration with brain iron accumulation, type 1 is characterized by -, -, and -synuclein neuropathology. American Journal of Pathology 157: 361–368.
    Gilman S, Low PA, Quinn N et al. (1999) Consensus statement on the diagnosis of multiple system atrophy. Journal of Neurological Sciences 163: 94–98.
    Gomez-Isla T, Irizarry MC, Mariash A et al. (2003) Motor dysfunction and gliosis with preserved dopaminergic markers in human -synuclein A30P transgenic mice. Neurobiology of Aging 24: 245–258.
    Gregory A and Hayflick SJ (2005) Neurodegeneration with brain iron accumulation. Folia Neuropathologica 43: 286–296.
    Heidebrink JL (2002) Is dementia with Lewy bodies the second most common cause of dementia? Journal of Geriatric Psychiatry and Neurology 15: 182–187.
    Jellinger KA (2003) Neuropathological spectrum of synucleinopathies. Movement Disorders 18(suppl. 6): S2–S12.
    Kahle PJ, Haass C, Kretzschmar H and Neumann M (2002) Structure/function of -synuclein in health and disease: rational development of animal models for Parkinson's and related diseases. Journal of Neurochemistry 82: 449–457.
    Kanda S, Bishop JF, Eglitis MA, Yang Y and Mouradian MM (2000) Enhanced vulnerability to oxidative stress by -synuclein mutations and C-terminal truncation. Neuroscience 97: 279–284.
    Krüger R, Kuhn W, Müller T et al. (1998) Ala30Pro mutation in the gene encoding -synuclein in Parkinson's disease. Nature Genetics 18: 106–108.
    Lee VMY and Trojanowski JQ (2006) Mechanisms of Parkinson's disease linked to pathological -synuclein: new targets for drug discovery. Neuron 52: 33–38.
    Lincoln SJ, Ross OA, Milkovic NM et al. (2007) Quantitative PCR-based screening of -synuclein multiplication in multiple system atrophy. Parkinsonism & Related Disorders 13: 340–342.
    Lippa CF, Duda JE, Grossman M et al. (2007) DLB and PDD boundary issues – diagnosis, treatment, molecular pathology, and biomarkers. Neurology 68: 812–819.
    Maraganore DM, de Andrade M, Elbaz A et al. (2006) Collaborative analysis of -synuclein gene promoter variability and Parkinson's disease. Journal of the American Medical Association 296: 661–670.
    Masliah E, Rockenstein E, Veinbergs I et al. (2000) Dopaminergic loss and inclusion body formation in -synuclein mice: implications for neurodegenerative disorders. Science 287: 1265–1269.
    Mizuta I, Satake W, Nakabayashi Y et al. (2006) Multiple candidate gene analysis identifies -synuclein as a susceptibility gene for sporadic Parkinson's disease. Human Molecular Genetics 15: 1151–1158.
    Moore DJ, West AB, Dawson VL and Dawson TM (2005) Molecular pathophysiology of Parkinson's disease. Annual Review of Neuroscience 28: 57–87.
    Murphy DD, Rueter SM, Trojanowski JQ and Lee VMY (2000) Synucleins are developmentally expressed, and -synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. Journal of Neuroscience 20: 3214–3220.
    Ostrerova N, Petrucelli L, Farrer M et al. (1999) -Synuclein shares physical and functional homology with 14-3-3 proteins. Journal of Neuroscience 15: 5782–5791.
    Ostrerova-Golts N, Petrucelli L, Hardy J et al. (2000) The A53T -synuclein mutation increases iron-dependent aggregation and toxicity. Journal of Neuroscience 20: 6048–6054.
    Ozawa T (2006b) Pathology and genetics of multiple system atrophy: an approach to determining genetic susceptibility spectrum. Acta Neuropathologica 115: 531–538.
    Ozawa T, Healy DG, Abou-Sleiman PM et al. (2006a) The -synuclein gene in multiple system atrophy. Journal of Neurology, Neurosurgery, and Psychiatry 77: 464–467.
    Polymeropoulos MH, Lavedan C, Leroy E et al. (1997) Mutation in the -synuclein gene identified in families with Parkinson's disease. Science 276: 2045–2047.
    van der Putten H, Wiederhold KH, Probst A et al. (2000) Neuropathology in mice expressing human -synuclein. Journal of Neuroscience 20: 6021–6029.
    Saito Y, Kawai M, Inoue K et al. (2000) Widespread expression of -synuclein and tau immunoreactivity in Hallervorden-Spatz syndrome with protacted clinical course. Journal of the Neurological Sciences 177: 48–59.
    Schapira AHV (2008) Mitochondria in the aetiology and pathogenesis of Parkinson's disease. The Lancet Neurology 7: 97–109.
    Senior SL, Ninkina N, Deacon R et al. (2008) Increased striatal dopamine release and hyperdopaminergic-like behaviour in mice lacking both -synuclein and -synuclein. European Journal of Neuroscience 27: 947–957.
    Sidhu A, Wersinger C and Vernier P (2004) -Synuclein regulation of the dopaminergic transporter: a possible role in the pathogenesis of Parkinson's disease. FEBS Letters 565: 1–5.
    Singleton A and Gwinn-Hardy K (2004) Parkinson's disease and dementia with Lewy bodies: a difference in dose? The Lancet 364: 1105–1107.
    Singleton AB, Farrer M, Johnson J et al. (2003) -Synuclein locus triplication causes Parkinson's disease. Science 302: 841.
    Spillantini MG, Divane A and Goedert M (1995) Assignment of human -synuclein (SNCA) and -synuclein (SNCB) genes to chromosomes 4q21 and 5q35. Genomics 27: 379–381.
    Spillantini MG, Schmidt ML, Lee VMY et al. (1997) -Synuclein in Lewy bodies. Nature 388: 839–840.
    Tan EK and Skipper LM (2007) Pathogenic mutations in Parkinson's disease. Human Mutation 28: 641–653.
    Tsuang DW, Dalan AM, Eugenio CJ et al. (2002) Familial dementia with Lewy bodies – a clinical and neuropathological study of 2 families. Archives of Neurology 59: 1622–1630.
    Uversky VN (2007) Neuropathology, biochemistry, and biphysics of -synuclein aggregation. Journal of Neurochemistry 103: 17–37.
    Vandrovcova J, Pittman AM, Malzer E et al. (2007) Association of MAPT haplotype-tagging SNPs with sporadic Parkinson's disease. Neurobiology of Aging doi:10.1016/j.neurobiolaging.2007.11.019.
    Wakabayashi K and Takahashi H (2006) Cellular pathology in multiple system atrophy. Neuropathology 26: 338–345.
    Wenning GK and Jellinger KA (2005) The role of -synuclein in the pathogenesis of multiple system atrophy. Acta Neuropathologica 109: 129–140.
    Yazawa I, Giasson B, Sasaki R et al. (2005) Mouse model of multiple system atrophy -synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron 45: 847–859.
    Yoshida M (2007) Multiple System Atrophy: -synuclein and neuronal degeneration. Neuropathology 27: 484–493.
    Zarranz JJ, Alegre J, Gómez-Esteban JC et al. (2004) The new mutation, E46K, of -synuclein causes Parkinson and Lewy body dementia. Annals of Neurology 55: 164–173.
 Further Reading
    Chesselet MF (2008) In vivo -synuclein overexpression in rodents: a useful model of Parkinson's disease? Experimental Neurology 209: 22–27.
    Cookson MR (2005) The biochemistry of Parkinson's disease. Annual Review of Biochemistry 74: 29–52.
    Halliday GM and McCann H (2008) Human-based studies on -synuclein deposition and relationship to Parkinson's disease symptoms. Experimental Neurology 209: 12–21.
    Lotharius J and Brundin P (2002) Pathogenesis of Parkinson's disease: dopamine, vesicles and -synuclein. Nature Reviews Neuroscience 3: 1–11.

Related Sub-Topics:

Neurobiology of Disease | Motor Systems | Molecular Genetics of Common and Complex Disease | Specific Genetic Disorders | Proteomic Studies of Genetic Disease | Proteins: Structure, Function, Metabolism
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Disorders with Synuclein Pathology and Parkinsonism
 
How to Cite close
Kilarski, Laura L, Buchman, Vladimir L, and Morris, Huw R(Mar 2009) Disorders with Synuclein Pathology and Parkinsonism. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006031]