α-synuclein, Lewy Bodies,
Prions, and Parkinson’s Disease
Cody McCullough & Sara Homsi
BCM 465
April 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!9
Dr. James Parkinson
A Few Famous People with PD
http://www.hipusa.com/webmd/images/health_and_medical_reference/brain_and_nerv
ous_system/Parkinsons_Disease_Frequently_Asked_Questions.jpg
Tyrosine hydroxylase
Tyrosine
http://en.wikipedia.org/wiki/File:L-tyrosine-skeletal.png
http://encefalus.com/wp-content/uploads/2008/09/dopamine.jpg
Dopamine
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
Synapse
α-synuclein
Neuron 2
Lewy Body Formation
Aggregation
A30P
E46K
A53T
Neuronal Cell Death ⁸, 9
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.
α-synuclein as a Prion?
• An infectious agent made up of protein
(PrPC)
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 culture⁴,⁵
Desplats Paper
• Demonstrates that nerve cells overexpressing αsynuclein 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
References
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Cookson, M.R. 2005. The biochemistry of Parkinson’s disease. Annu. Rev.
Biochem. 74: 29-52.
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.
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.
Lee, H-J., et al. 2008. Assembly-dependent endocytosis and clearance of
extrancellular α-synuclein. Int J Biochem Cell Biol 40: 1835-1849.
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.
Olanowa, C.W., and S.B. Prusiner. 2009. Is Parkinson’s disease a prion
disorder? PNAS 106: 12571-12571.
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.
Wood-Kaczmar, A., Gandhi, S., and N.W. Wood. 2006. Understanding the
molecular causes of Parkinson’s disease. Trends Mol. Med. 12: 521-528.
Brown University, Deep Brain Stimulation: Parkinson's Disease