New evidence on α-synuclein and Tau binding to conformation and sequence specific GCFNx01 rich DNA: Relevance to neurological disorders

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.

Chromatin-Bound Oxidized α-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson’s Disease

“…In cells, α-Syn folding could be promoted by accumulated redox active metal ions, as was reported by our lab [60, 61] and others [9, 10]. In addition to α-Syn, Aβ, tau and prion proteins implicated in AD and prion diseases, also have DNA binding activity, suggesting that DNA binding is a common property of many amyloidogenic proteins associated with various neurodegenerative disorders [28, 62–64]. However, the role of their DNA binding in disease pathology has not been well studied.…”

“…Interestingly, a recent study shows that α-Syn selectively binds to promoter regions of several genes in oxidatively stressed cells, suggesting its involvement in transcriptional regulation [21]. We previously showed affinity of α-Syn for guaninecytosine-rich DNA sequences, a scenario consistent with its proposed promoter activity [28]. …”

Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?

“…Furthermore, the Aβ peptides were shown to acquire DNA nicking activity, particularly in the presence of pro-oxidant metal ions in vitro [190]. Aβ (1-42) and Aβ (1–16) fragments, misfolded α-Syn and tau bind to GC-rich DNA and also alter the conformation of DNA, which could impact gene expression patterns [191, 192]. Studies have shown that prion proteins also have DNA-binding properties [193], which in turn induces structural changes in prion peptides by forming stable complexes causing further polymerization [194].…”

Nuclear Lipids in the Nervous System: What they do in Health and Disease

“…Interestingly, oxidative stress that is often correlated with neurodegeneration, down-regulates PLCβ1 thereby promoting α-synuclein aggregation [28]. Nuclear -synuclein inhibits histone acetylation and promotes death in SH-SY5Y neuroblastoma cells while cytoplasmatic -synuclein is neuroprotective [29];-synuclein binds to DNA in a conformation-specific manner and causes a conformational transition that could play a significant role in neuronal cell dysfunction [30]. It is worth noting that synuclein has been found in the nuclei of some neurons and oligodendroglia from brains of patients with multiple system atrophy [31,32].…”