α-synuclein, Lewy Bodies, Prions, and Parkinson’s

Disease Cody McCullough & Sara Homsi

BCM 465April 19th, 2010

Parkinson’s Disease

• 1817: James Parkinson • Progressive

neurodegenerative disorder

• 1.5 million Americans • 85% are over age 65 • 60,000 new cases / year!

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Dr. James Parkinson

A Few Famous People with PD

http://www.hipusa.com/webmd/images/health_and_medical_reference/brain_and_nervous_system/Parkinsons_Disease_Frequently_Asked_Questions.jpg

Tyrosine Dopamine

Tyrosine hydroxylase

http://en.wikipedia.org/wiki/File:L-tyrosine-skeletal.png

http://encefalus.com/wp-content/uploads/2008/09/dopamine.jpg

http://www.oralchelationblog.com/wp-content/uploads/2008/08/parkinsonsdopamine.jpg

What causes PD?

Lewy Bodies

• Abnormal aggregates of proteins that develop inside nerve cells

• α-synuclein aggregates + ubiquitin¹

http://en.wikipedia.org/wiki/File:Lewy_Koerperchen.JPG

What is α-synuclein?

• Small protein: 14kDa

• Encoded by SNCA gene

• Highly conserved; expressed in brain¹,⁷

http://www.bio.purdue.edu/people/faculty/cramer/images/Alpha-Synuclein.jpg

α-synuclein transmission

Neuron 1

Neuron 2

α-synuclein

Synapse

Lewy Body Formation

Neuronal Cell Death ⁸, 9

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Savitt, J.M., V.L. Dawson, and T.M. Dawson. 2006. Diagnosis and treatment of Parkinson’s disease: molecules to medicine. J. Clin. Invest. 116: 1744-1754.

Aggregation

α-synuclein as a Prion?

• An infectious agent made up of protein (PrPC)o α-helical conformationo β-sheet conformation amyloid fibrils 6

• Aggregation & transmission of the misfolded protein thought to be toxic

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Previous Findings

• α-synuclein and its aggregates can be exocytosed from neuronal cells³

• α-synuclein and its aggregates can be endocytosed by neurons in culture⁴,⁵

• 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. 2005. The biochemistry of Parkinson’s disease. Annu.

Rev. Biochem. 74: 29-52. 2. Desplats, P., Lee, H-J., Bae, E-J., Patrick, C., Rockenstein, E., Crews,

L., Spencer, B., Masliah, E., and S-J. 2009. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein. PNAS 106: 13010-13015.

3. Lee, H-J., Patel, S., and S-J. Lee. 2005. Intravascular localization and exocytosis of α-synuclein and its aggregates. J Neurosci 25: 6016-6024.

4. Lee, H-J., et al. 2008. Assembly-dependent endocytosis and clearance of extrancellular α-synuclein. Int J Biochem Cell Biol 40: 1835-1849.

5. Lee, H-J., Suk, J.E., Bae, E.J., and S-J. Lee. 2008. Clearance and deposition of extracellular α-synuclein aggregates in microglia. Biochem Biophys Res Commun 372: 423-428.

6. Olanowa, C.W., and S.B. Prusiner. 2009. Is Parkinson’s disease a prion disorder? PNAS 106: 12571-12571.

7. Savitt, J.M., Dawson, V.L., and T.M. Dawson. 2006. Diagnosis and treatment of Parkinson’s disease: molecules to medicine. J. Clin. Invest. 116: 1744-1754.

8. Wood-Kaczmar, A., Gandhi, S., and N.W. Wood. 2006. Understanding the molecular causes of Parkinson’s disease. Trends Mol. Med. 12: 521-528.

9. Brown University, Deep Brain Stimulation: Parkinson's Disease