Journal of Pharmacy And Bioallied Sciences

ORIGINAL ARTICLE
Year
: 2012  |  Volume : 4  |  Issue : 2  |  Page : 112--117

New evidence on α-synuclein and Tau binding to conformation and sequence specific GC* rich DNA: Relevance to neurological disorders


P Vasudevaraju1, Erika Guerrero2, Muralidhar L Hegde3, TB Collen4, Gabrielle B Britton2, KS Rao2 
1 Department of Neuroscience, Medical University of South Carolina, Charleston, USA
2 Centre for Neuroscience, Institute for Scientific Research and Technological Services (INDICASAT-AIP), City of Knowledge, Republic Panama
3 Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, USA
4 Clinical Biochemistry, Columbus Medical School, Republic Panama

Correspondence Address:
K S Rao
Centre for Neuroscience, Institute for Scientific Research and Technological Services (INDICASAT-AIP), City of Knowledge
Republic Panama

Background: Deoxyribonucleic acid (DNA) topology plays a critical role in maintaining the integrity of the genome and cellular functions. Although changes in DNA conformation and structural dynamics in the brain have been associated with various neurological disorders, its precise role in the pathogenesis is still unclear. Previous studies from our laboratory have shown that there is a conformational change in the genomic DNA of Parkinson«SQ»s disease (PD) (B to altered B-DNA) and Alzheimer«SQ»s disease brain (B to Z-DNA). However, there is limited information on the mechanism on DNA dynamics changes in brain. Objective: In the present study, we have investigated the DNA conformation and sequence specific binding ability of α-Synuclein and Tau with reference to B-DNA and Z-DNA using oligonucleotide (CGCGCGCG) 2 as a novel model DNA system. This sequence is predominantly present in the promoter region of the genes of biological relevance. Materials and Methods: Natively, (CGCGCGCG) 2 sequence exists in B-DNA conformation, but in the presence of high sodium concentration (4 M NaCl), the oligo converts into Z-DNA form. We used circular dichroism, melting temperature and fluorescence studies to understand protein-DNA interactions. Results: CD studies indicated that both α-Synuclein and Tau bind to B-DNA conformation of (CGCGCGCG) 2 and induce altered B-form. Further, these proteins increased the melting temperature and decreased the number of EtBr molecules bound per base pair of DNA in B-form indicating that DNA stability is favored to alter B-DNA conformation, which could be an intermediate form favoring Z-DNA conformation. Moreover, both α-Synuclein and Tau also bound to disease-linked Z-DNA conformation of (CGCGCGCG) 2 and further stabilized the Z-conformation. Conclusions: The present study provides vital mechanistic information on Synuclein and Tau binding to DNA in a conformation-specific manner causing conformational transition. Furthermore, both the proteins stabilize Z-DNA conformation. These have altered minor and major groove patterns and thus may have significant biological implications in relevance to gene expression pattern in neurodegeneration. We discuss the implications of α-Synuclein/Tau binding to DNA and stabilizing the altered conformations of DNA in neuronal cell dysfunction.


How to cite this article:
Vasudevaraju P, Guerrero E, Hegde ML, Collen T B, Britton GB, Rao K S. New evidence on α-synuclein and Tau binding to conformation and sequence specific GC* rich DNA: Relevance to neurological disorders.J Pharm Bioall Sci 2012;4:112-117


How to cite this URL:
Vasudevaraju P, Guerrero E, Hegde ML, Collen T B, Britton GB, Rao K S. New evidence on α-synuclein and Tau binding to conformation and sequence specific GC* rich DNA: Relevance to neurological disorders. J Pharm Bioall Sci [serial online] 2012 [cited 2020 Nov 24 ];4:112-117
Available from: https://www.jpbsonline.org/article.asp?issn=0975-7406;year=2012;volume=4;issue=2;spage=112;epage=117;aulast=Vasudevaraju;type=0