Introduction

1. The Role of α-synuclein in Parkinson’s DiseaseKatherine Hamilton, Department of Biochemistry, Bryn Mawr College Mechanism of α-synuclein Aggregation Introduction References A Potential Modifier of α-synucelin Toxicity Protein Misfolding in PD Toxic Effects of α-synuclein Oligomers • Parkinson’s Disease (PD) is the most common neurodegenerative movement disorder, affecting 1% of people over 50. • Symptoms: • Slowness of movement (Bradykinesia) • Difficulty initiating willed movement (Akinesia) • Rigidity • Tremors of the hands and jaw • PD arises from degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta. • Current Treatments: • Administration of L-Dopa (precursor to DA) or DA analogues • Deep Brain Stimulation Dopamine Phosphorylation Chen and Feany (2005) Preventing phosphorylation at Ser129 of α-synuclein suppresses DA cell loss produced by expression of human α-synuclein, while mimicking phosphorylation at Ser120 accelerates neuronal loss in Drosophila. Xu et al. (2002) Apoptosis after transfection with α-synuclein constructs is significantly decreased after treatment with DA inhibitor in human dopaminergic cells. The Basal Ganglia Motor Loop Conclusions and Directions for Future Research • Misfolding of α-synuclein  formation of toxic protofibrils  disrupted ion permeability  degeneration of DA neurons • This is only one pathway proposed as a cause of PD. Several other toxins and proteins besides α-synuclein have been studied. • Potential therapeutic opportunities: • Targeting α-synuclein soluble oligomers (or eliminating all α-synuclein expression). • Altering modification of α-synuclein toxicity (ex. kinase inhibitors). Bear, Connors, and Paradiso (2001) Cookson (2009) • Amyloidoses: disorders in which protein misfolding leads to aggregation of insoluble amyloid fibers. • In PD, the misfolded form of α-synuclein protein aggregates into masses called Lewy bodies. • Evidence: • Postmortem brains of PD patients characterized by presence of Lewy bodies. • Familial PD caused by three point mutations in α-synuclein gene: A53T, A30P, and E46K. Bear, MF, Connors, BW, Paradiso, MA. 2001. Neuroscience: Exploring the brain. Baltimore, MD: Lippincott Williams & Wilkins. p 477-482. Chen, L, Feany, MB. 2005. Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson Disease. Nature Neuroscience 8:657-63. Conway, KA, Lee, S, Rochet, J, Ding, TT, Williamson, RE, Lansbury, PT. 2000. Acceleration of oligomerization, not fibrillization, is a shared property of both α-synuclein mutations linked to early-onset Parkinson’s disease: Implications for pathogenesis and therapy. Proceedings of the National Academy of Sciences 97:571-576. Cookson, MR. 2009. α-synuclein and neuronal cell death. Molecular Neurodegeneration 4:1-14. Devine, MJ, Lewis, PA. 2008. Emerging pathways in genetic Parkinson’s disease: tangles, Lewy bodies and LRRK2. Federation of European Biochemical Societies 275: 5748-5757. Furukawa, K, Matsuzaki-Kobayashi, M, Hasegawa, T, Kikuchi, A, Sugeno, N,Itoyama, Y, et al. 2006. Plasma membrane ion permeability induced by mutant α-synuclein contributes to the degeneration of neural cells. Journal of Neurochemistry 97:1071-1077. Lashuel, HA, Harltley, D, Petre, BM, Walz, T, Lansbury, PT. 2002. Amyloid pores from pathogenic mutations. Nature 418: 291. Nelson, DL, Cox, MM. 2008. Lehninger principles of biochemistry. New York, NY: W.H. Freeman and Company. p 145-147. Periquet, M, Fulga, T, Myllykangas, L, Schlossmacher, MG, Feany, MB. 2007. Aggregated α-synuclein mediates dopaminergic neurotoxicity in vivo. Polymeropoulos, MH, Lavedan, C, Leroy, E, Ide,SE, Dehejia, A, Dutra, A, et al. 1997. Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science 276:2045-2047. Xu, J, Kao, S, Lee, FJS, Song, W, Jin, L, Yankner, BA. 2002. Dopamine-dependent neurotoxicity of α-synuclein: A mechanism for selective neurodegeneration in Parkinson disease. Nature Medicine 8: 600-606. Vesicles Mitochondria ER α-synuclein protofibrils Amyloid pores Cell membrane Toxic species = oligomeric form of α-synuclein (protofibrils). β-sheet-rich protofibrils can interact with lipids and form pore-like structures. This may lead to disrupted permeability in various cell components.