Disorders with Synuclein Pathology and Parkinsonism

Abstract

A variety of neurodegenerative disorders are classified as synucleinopathies based on the presence of prominent α‐synuclein pathology. These diseases include Parkinson disease (PD), dementia with Lewy bodies (with neuronal Lewy body formation) and multiple system atrophy (with glial cytoplasmic inclusions). The normal function of α‐synuclein includes regulation of presynaptic vesicles. Autosomal dominant PD can be due to coding mutations or multiplications of the α‐synuclein gene (SNCA). The coding mutations are thought to lead to a gain of function, in particular acceleration of the formation of protofibrils. 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. α‐Synuclein is now recognised as the key component of Lewy bodies and as an important target for therapeutic intervention. A number of α‐synuclein antibody therapy treatments are in development and have entered early‐phase clinical development.

Key Concepts

  • α‐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 α‐synuclein is incompletely understood but is likely to involve interaction with and regulation of synaptic vesicles.
  • There is some evidence that α‐synuclein may have a role as a cellular chaperone and in interacting with the proteasome.
  • Mendelian coding mutations in the α‐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 α‐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.
  • There is now substantial evidence for cell‐to‐cell ‘prion‐like’ spread of synuclein pathology in the brain.
  • This spreading pathology represents a therapeutic target, and a number of anti‐α‐synuclein antibody therapies are in early‐stage clinical trial development.

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

Figure 1. Structure of α‐synuclein showing the location of the Mendelian coding mutations. Kindly provided by Dr Morris.
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References

Abeliovich A, Schmitz Y, Farina I, et al. (2000) Mice lacking α‐synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25: 239–252.

Al‐Chalabi A, Dürr A, Wood NW, et al. (2009) Genetic variants of the alpha‐synuclein gene SNCA are associated with multiple system atrophy. PLoS One 4: e7114.

Beyer K (2006) α‐synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers. Acta Neuropathologica 112: 237–251.

Brundin P, Dave KD and Kordower JH (2017) Therapeutic approaches to target alpha‐synuclein pathology. Experimental Neurology 298: 225–235.

Cabin DE, Shimazu K, Murphy D, et al. (2002) Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking α‐synuclein. Journal of Neuroscience 22: 8797–8807.

Chandra S, Gallardo G, Fernández‐Chacón R, Schlüter O and Südhof T (2005) α‐synuclein cooperates with CSP in preventing neurodegeneration. Cell 123: 383–396.

Chang D, Nalls MA, Hallgrímsdóttir IB, et al. (2017) A meta‐analysis of genome‐wide association studies identifies 17 new Parkinson's disease risk loci. Nature Genetics 49: 1511–1516.

Chiba‐Falek O and Nussbaum RL (2003) Regulation of α‐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 α‐synuclein. FEBS Letters 576: 363–368.

Drolet RE, Behrouz B, Lookingland KJ and Goudreau JL (2004) Mice lacking α‐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 α‐synuclein genomic multiplications. Annals of Neurology 55: 174–179.

Federoff M, Schottlaender LV, Houlden H and Singleton A (2015) Multiple system atrophy: the application of genetics in understanding etiology. Clinical Autonomic Research 25: 19–36.

Federoff M, Price TR, Sailer A, et al. (2016) Genome‐wide estimate of the heritability of multiple system atrophy. Parkinsonism & Related Disorders 22: 35–41.

Fuchs J, Tichopad A, Golub Y, et al. (2008) Genetic variability in the SNCA gene influences α‐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 ‐α, β‐, and γ‐synuclein neuropathology. American Journal of Pathology 157: 361–368.

Games D, Valera E, Spencer B, et al. (2014) Reducing C‐terminal‐truncated alpha‐synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson's disease‐like models. Journal of Neuroscience 34: 9441–9454.

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 α‐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.

Hardy J and Revesz T (2012) The spread of neurodegenerative disease. New England Journal of Medicine 366: 2126–2128.

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 α‐synuclein in health and disease: rational development of animal models for Parkinson's and related diseases. Journal of Neurochemistry 82: 449–457.

Kiely AP, Ling H, Asi YT, et al. (2015) Distinct clinical and neuropathological features of G51D SNCA mutation cases compared with SNCA duplication and H50Q mutation. Molecular Neurodegeneration 10: 41.

Kingwell K (2017) Zeroing in on neurodegenerative α‐synuclein. Nature Reviews. Drug Discovery 16: 371–373.

Krüger R, Kuhn W, Müller T, et al. (1998) Ala30Pro mutation in the gene encoding α‐synuclein in Parkinson's disease. Nature Genetics 18: 106–108.

Lee VMY and Trojanowski JQ (2006) Mechanisms of Parkinson's disease linked to pathological α‐synuclein: new targets for drug discovery. Neuron 52: 33–38.

Li JY, Englund E, Holton JL, et al. (2008) Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host‐to‐graft disease propagation. Nature Medicine 14: 501–503.

Lincoln SJ, Ross OA, Milkovic NM, et al. (2007) Quantitative PCR‐based screening of α‐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.

Luk KC, Kehm VM, Zhang B, et al. (2012) Intracerebral inoculation of pathological α‐synuclein initiates a rapidly progressive neurodegenerative α‐synucleinopathy in mice. Journal of Experimental Medicine 209: 975–986.

Maraganore DM, de Andrade M, Elbaz A, et al. (2006) Collaborative analysis of α‐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 α‐synuclein mice: implications for neurodegenerative disorders. Science 287: 1265–1269.

Mizuta I, Satake W, Nakabayashi Y, et al. (2006) Multiple candidate gene analysis identifies α‐synuclein as a susceptibility gene for sporadic Parkinson's disease. Human Molecular Genetics 15: 1151–1158.

Murphy DD, Rueter SM, Trojanowski JQ and Lee VMY (2000) Synucleins are developmentally expressed, and α‐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) α‐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 α‐synuclein mutation increases iron‐dependent aggregation and toxicity. Journal of Neuroscience 20: 6048–6054.

Ozawa T, Healy DG, Abou‐Sleiman PM, et al. (2006) The α‐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 α‐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 α‐synuclein. Journal of Neuroscience 20: 6021–6029.

Sailer A, Scholz SW, Nalls MA, et al. (2016) A genome‐wide association study in multiple system atrophy. Neurology 87: 1591–1598.

Saito Y, Kawai M, Inoue K, et al. (2000) Widespread expression of α‐synuclein and tau immunoreactivity in Hallervorden‐Spatz syndrome with protracted clinical course. Journal of the Neurological Sciences 177: 48–59.

Schenk DB, Koller M, Ness DK, et al. (2017) First‐in‐human assessment of PRX002, an anti‐α‐synuclein monoclonal antibody, in healthy volunteers. Movement Disorders 32: 211–218.

Scholz SW, Houlden H, Schulte C, et al. (2009) SNCA variants are associated with increased risk for multiple system atrophy. Annals of Neurology 65: 610–614.

Senior SL, Ninkina N, Deacon R, et al. (2008) Increased striatal dopamine release and hyperdopaminergic‐like behaviour in mice lacking both α‐synuclein and γ‐synuclein. European Journal of Neuroscience 27: 947–957.

Sidhu A, Wersinger C and Vernier P (2004) α‐synuclein regulation of the dopaminergic transporter: a possible role in the pathogenesis of Parkinson's disease. FEBS Letters 565: 1–5.

Singleton AB, Farrer M, Johnson J, et al. (2003) α‐synuclein locus triplication causes Parkinson's disease. Science 302: 841.

Singleton A and Gwinn‐Hardy K (2004) Parkinson's disease and dementia with Lewy bodies: a difference in dose? The Lancet 364: 1105–1107.

Spillantini MG, Schmidt ML, Lee VMY, et al. (1997) α‐synuclein in Lewy bodies. Nature 388: 839–840.

Spillantini MG and Goedert M (2017) Neurodegeneration and the ordered assembly of α‐synuclein. Cell and Tissue Research. DOI: 10.1007/s00441-017-2706-9. [Epub ahead of print].

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 α‐synuclein aggregation. Journal of Neurochemistry 103: 17–37.

Vandrovcova J, Pittman AM, Malzer E, et al. (2009) Association of MAPT haplotype‐tagging SNPs with sporadic Parkinson's disease. Neurobiology of Aging 30: 1477–1482.

Watts JC, Giles K, Oehler A, et al. (2013) Transmission of multiple system atrophy prions to transgenic mice. PNAS 110: 19555–19560.

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 α‐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 α‐synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron 45: 847–859.

Yoshida M (2007) Multiple System Atrophy: α‐synuclein and neuronal degeneration. Neuropathology 27: 484–493.

Zarranz JJ, Alegre J, Gómez‐Esteban JC, et al. (2004) The new mutation, E46K, of α‐synuclein causes Parkinson and Lewy body dementia. Annals of Neurology 55: 164–173.

Further Reading

Bonifati V (2008) Recent advances in the genetics of dementia with Lewy bodies. Current Neurology and Neuroscience Reports 8: 187–189.

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.

Kanda S, Bishop JF, Eglitis MA, Yang Y and Mouradian MM (2000) Enhanced vulnerability to oxidative stress by α‐synuclein mutations and C‐terminal truncation. Neuroscience 97: 279–284.

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Kilarski, Laura L, Zhang, Wei, and Morris, Huw R(Jun 2018) Disorders with Synuclein Pathology and Parkinsonism. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006031.pub2]