[Frontiers in Bioscience 15, 418-436, January 1, 2010]

DNA induced folding/fibrillation of alpha-synuclein: new insights in Parkinson's disease

Muralidhar L. Hegde1, Padmaraju Vasudevaraju1 , Kosagisharaf Jagannatha Rao1

1Department of Biochemistry and Nutrition, Central Food Technological Research Institute (CSIR unit), Mysore-570020, India


1. Abstract
2. Introduction
2.1. General characteristics of PD
2.1.1. Pathology: Lewy bodies
2.2. Oxidative stress and DNA damage in PD
2.3. Cause: cross-talk of environment and genome
3. alpha-Synuclein and PD
3.1. Potential normal functions of alpha-Synuclein
3.2.alpha-synuclein toxicity in diffuse Lewy body disease
4. Expression and subcellular distribution of alpha-Synuclein
4.1. Nuclear localization of alpha-Synuclein
4.1.1. Nuclear transport of alpha-Synuclein
4.2. alpha-Synuclein genotoxicity
5. alpha-Synuclein-DNA interactions-new concept
5.1. Our hypothesis on DNA binding of alpha-Synuclein- genesis of model
5.3. First evidence for DNA binding property of alpha-Synuclein
5.4. alpha-Synuclein affects DNA conformation
5.5. DNA induced folding of alpha-Synuclein
5.6. alpha-Synuclein aggregation and DNA binding
6. Our model on genotoxicity of alpha-Synuclein
7. Is DNA binding common property of many amyloidogenic proteins?
8. Biological significance of DNA binding of alpha-Synuclein
9. Alternative view: alpha-Synuclein and neuroprotection
10. Perspectives and future directions
11. Acknowledgements
12. References


Emerging evidences on the nuclear localization of alpha-Synuclein in neurons and a close look in to its primary sequence/structural organization led us to examine its DNA binding ability. Subsequently, we first time demonstrated the interaction of DNA with alpha-Synuclein which was also confirmed by others. We recently showed that double-stranded oligos induce partial folding in alpha-Synuclein and promote its aggregation, where as single-strand circular DNA and supercoiled plasmid DNA induced a helix-rich conformation and protected the protein from fibrillation. In turn, alpha-Synuclein modulates DNA conformation from B- to an altered B-form, which may affect DNA transactions. Interestingly, amyloid-beta peptides and prion proteins implicated in Alzheimer's disease and Prion diseases respectively, were also shown to have DNA binding activity which suggests that DNA binding may be a common property of many amyloidogenic proteins associated with various neurodegenerative disorders. In this review, we debate the biological significance of DNA-alpha-Synuclein interactions; it's beneficial vs. toxic role in relevance to Parkinson's disease.