Studies on Chromatin Organization and the role of Curcumin in Chromatin Stability in Relevance to Neurodegeneration

Vasudeva Raju, P. (2011) Studies on Chromatin Organization and the role of Curcumin in Chromatin Stability in Relevance to Neurodegeneration. PhD thesis, University of Mysore.

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Abstract

The progressive loss of structure and function of neurons is the final consequence of the all neurodegenerative diseases like Parkinson’s disease (PD). Genomic integrity is essential for the proper functioning of the neuronal cell and altered genomic integrity lead to neurodegeneration. DNA in eukaryotic cell is arranged in the form of compactly condensed state known as chromatin. Chromatin organization was a dynamic process occurring in the living cells by continuously opening and reorganizing according to the cellular needs. Chromatin organization plays an important role in regulation of the gene expression. Chromatin organization was altered in Parkinson’s disease. Histone H3 was acetylated in all the PD chromatin samples compared to 50% of histone acetylation levels in the control sample. DNA methylation was more in PD DNA compared to that of control. Micrococcal nuclease digestion revealed that looser chromatin loops were present in PD chromatin compared to control. The levels of 8-OHdG (Oxidative DNA damage biomarker) were increased in PD patients compared to control indicating more genotoxicity in brain cells. MRI analysis of PD patients brain showed atrophy in caudate nucleus, thalamus, hippocampus and substantia nigra regions compared to control. Trace metals like Fe and Cu were increased, while Zn levels were decreased in aging brain. Single strand breaks and double strand breaks were accumulated in frontal cortex and hippocampus of aging brain. Neuroproteins like a-synuclein, tau and neuromelanin were involved in the pathogenesis of PD. As these neuroproteins are localized in the nuclear region, they may have a role in nuclear functions. We showed that a-synuclein, Tau and neuromelanin bound to supercoiled DNA and nick the DNA like endonuclease. These neuroproteins altered the DNA integrity indicating their genotoxic role. a-synuclein and Tau bind to conformation and sequence specific oligonucleotides of both in B-DNA and biologically significant Z-form. Curcumin, a dietary polyphenol is the principle component of the rhizome (turmeric) of the herb Curcuma longa. Curcumin altered chromatin organization and destabilized the chromatin. Curcumin binds to DNA and altered DNA integrity. Curcumin also destabilized the Tau-DNA, a-synuclein-DNA complexes. The present investigation provides a new evidence on the pathological mechanism in PD.

Item Type:	Thesis (PhD)
Uncontrolled Keywords:	Parkinson’s disease, Neurodegeneration, curcumin, chromatin
Subjects:	500 Natural Sciences and Mathematics > 07 Life Sciences > 03 Biochemistry & Molecular Biology
Divisions:	Dept. of Biochemistry
Depositing User:	Food Sci. & Technol. Information Services
Date Deposited:	16 May 2012 04:49
Last Modified:	16 May 2012 04:49
URI:	http://ir.cftri.res.in/id/eprint/10766

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