α-synuclein, Lewy Bodies, Prions, and Parkinson’s Disease Cody McCullough & Sara Homsi BCM 465 April 19 th, 2010

Parkinson’s Disease 1817: James Parkinson Progressive neurodegenerative disorder 1.5 million Americans 85% are over age 65 60,000 new cases / year! 9 Dr. James Parkinson

A Few Famous People with PD

ous_system/Parkinsons_Disease_Frequently_Asked_Questions.jpg

Tyrosine Dopamine Tyrosine hydroxylase

What causes PD?

Lewy Bodies Abnormal aggregates of proteins that develop inside nerve cells α-synuclein aggregates + ubiquitin¹

What is α-synuclein? Small protein: 14kDa Encoded by SNCA gene Highly conserved; expressed in brain¹, ⁷

α-synuclein transmission Neuron 1 Neuron 2 α-synuclein Synapse

Lewy Body Formation Neuronal Cell Death ⁸, 9 A30P E46K A53T Savitt, J.M., V.L. Dawson, and T.M. Dawson Diagnosis and treatment of Parkinson’s disease: molecules to medicine. J. Clin. Invest. 116: Aggregation

α-synuclein as a Prion? An infectious agent made up of protein (PrP C ) o α-helical conformation o β-sheet conformation  amyloid fibrils 6 Aggregation & transmission of the misfolded protein thought to be toxic 6

Previous Findings α-synuclein and its aggregates can be exocytosed from neuronal cells³ α-synuclein and its aggregates can be endocytosed by neurons in culture ⁴, ⁵

Demonstrates that nerve cells overexpressing α- synuclein can transmit the protein to healthy grafted neural stem cells in both in vitro and in vivo models² Tests if α-synuclein pathology involves direct neuron-to-neuron transmission of α-synuclein aggregates via endocytosis “There is much to suggest that α-synuclein behaves like a prion.” 6 Desplats Paper

References 1.Cookson, M.R The biochemistry of Parkinson’s disease. Annu. Rev. Biochem. 74: Desplats, P., Lee, H-J., Bae, E-J., Patrick, C., Rockenstein, E., Crews, L., Spencer, B., Masliah, E., and S-J Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein. PNAS 106: Lee, H-J., Patel, S., and S-J. Lee Intravascular localization and exocytosis of α-synuclein and its aggregates. J Neurosci 25: Lee, H-J., et al Assembly-dependent endocytosis and clearance of extrancellular α-synuclein. Int J Biochem Cell Biol 40: Lee, H-J., Suk, J.E., Bae, E.J., and S-J. Lee Clearance and deposition of extracellular α-synuclein aggregates in microglia. Biochem Biophys Res Commun 372: Olanowa, C.W., and S.B. Prusiner Is Parkinson’s disease a prion disorder? PNAS 106: Savitt, J.M., Dawson, V.L., and T.M. Dawson Diagnosis and treatment of Parkinson’s disease: molecules to medicine. J. Clin. Invest. 116: Wood-Kaczmar, A., Gandhi, S., and N.W. Wood Understanding the molecular causes of Parkinson’s disease. Trends Mol. Med. 12: Brown University, Deep Brain Stimulation: Parkinson's Disease