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. 2012 Apr;4(2):112-7.
doi: 10.4103/0975-7406.94811.

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

P Vasudevaraju  1 , Erika Guerrero, Muralidhar L Hegde, T B Collen, Gabrielle B Britton, K S Rao
Affiliations

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

P Vasudevaraju et al. J Pharm Bioallied Sci. 2012 Apr.

Abstract

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's disease (PD) (B to altered B-DNA) and Alzheimer'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.

Keywords: Alzheimer's disease; Parkinson's disease; Tau; Z-DNA; oligonucleotide-protein interaction; α-Synuclein.

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Conflict of interest statement

Conflict of Interest: None declared.

Figures

Figure 1
Figure 1
Circular dichroism spectroscopy of (CGCGCGCG)2 oligonucleotide complexes. (a) (CGCGCGCG)2 oligonucleotide in B-DNA conformation and Z-DNA conformation. (b) α-Synuclein induced altered B-conformation in B-DNA of (CGCGCGCG)2. (c) Tau induced altered B-conformation in B-DNA of (CGCGCGCG)2. (d) α-Synuclein - Z-DNA of (CGCGCGCG)2 complex in Z-DNA conformation. (e) Tau - Z-DNA of (CGCGCGCG)2 complex in Z-DNA conformation
Figure 2
Figure 2
Melting temperature curves of (CGCGCGCG)2 oligonucleotide complexes. (a) Melting temperature (Tm) curve of (CGCGCGCG)2 oligonucleotide in B-DNA and Z-DNA conformations, respectively. (b) Melting temperature (Tm) curve of (CGCGCGCG)2 oligonucleotide in B-DNA and B-DNA-α-Synuclein complex (mass ratio 1:2). (c) Melting temperature (Tm) curve of (CGCGCGCG)2 oligonucleotide in B-DNA and B-DNA-Tau complex (mass ratio 1:2). (d) Melting temperature (Tm) curve of (CGCGCGCG)2 oligonucleotide in Z-DNA and Z-DNA- α-Synuclein complex (mass ratio 1:2). (e) Melting temperature (Tm) curve of (CGCGCGCG)2 oligonucleotide in Z-DNA and Z-DNA-Tau complex (mass ratio 1:2)
Figure 3
Figure 3
Our hypothesis on the potential implications of sequence specific binding of α-Synuclein/Tau in neuronal cell death. Both α-Synuclein/Tau may bind to CG rich regions in the promoters of various genes and alter the conformation from B-DNA to altered B-DNA. The altered conformation in the promoter region could alter the binding of transcription factors and alter gene expression. The altered regulation of the gene expression may result in neuronal cell dysfunction and finally lead to neuronal cell death. The negative supercoils generated during transcription may induce the formation of Z-DNA in CG rich regions. Normally, after transcription the negative supercoils are relaxed and the Z-DNA is again converted to B-DNA. Both α-Synuclein/Tau may bind to Z-DNA conformation formed due to transcriptional stress and stabilize the Z-DNA conformation. Z-DNA stabilization may result in the inhibition of transcription factors binding or may stop the movement of RNA polymerase. This may lead to the suppression of genes and finally to neuronal cell dysfunction
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