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

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.