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Studies on alpha-Synuclein Aggregation and the effect of Dietary Curcumin Derivative: Relevance to Parkinson’s Disease
Ms., Bharathi (2007) Studies on alpha-Synuclein Aggregation and the effect of Dietary Curcumin Derivative: Relevance to Parkinson’s Disease. PhD thesis, University of Mysore.
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Abstract
Parkinson's disease (PD) is a devastating and complex neurological disorder that results from the progressive degeneration of nerve cells (neurons) in a region of the brain viz. Substantia nigra that controls movement. The pathological hallmark of PD is the formation of insoluble protein aggregates known as Lewy bodies. The major constituent of these fibrillar structures is -synuclein, a 140 amino acid protein with a basic amino terminal and an acidic carboxy terminal. alpha-synuclein undergoes self-association i.e. it tends to aggregate to form insoluble forms. The aggregation kinetics of alpha-synuclein is complex in nature and involves multi-step process from soluble monomer to insoluble fibrillar aggregates through the formation of toxic intermediate oligomeric species and protofibrils. In the present investigation, we developed a novel analytical mathematical model to understand the self-association pathway, with the formation of different fibrillar species at each interval, also in identifying the different species (monomer, oligomer, fibrils) at certain time. Metals are known to enhance the aggregation of -synuclein. MALDI-TOF, TEM, Fluorescence etc. studies showed that Fe (III), Fe (II) is the most potent enhancer of -synuclein aggregation compared to Cu (II), Cu (III). Based on the electron microscopic images that the morphology of the -synuclein [wild type, A30P, A53T, E46K mutant forms] fibrils with Cu and Fe are found to be diverse. To understand the above mechanism, we have employed thermodynamics parameters to elucidate the binding efficacy of the metals to alpha-synuclein. Micro-Calorimetry studies revealed that Cu (II) with alpha-synuclein monomer (wild and mutant forms) showed i) two binding sites, while, Fe (III) with alpha-synuclein yields single binding site. We have characterized and elucidated the novel properties of Curc-gluc. Curc-gluc acts as an anti-aggregating agent and by inhibiting oligomer formation and in turn fibril formation, might aid the development of disease modifying agents in preventing or treating PD.
| Item Type: | Thesis (PhD) |
|---|---|
| Uncontrolled Keywords: | alpha-synuclein Parkinson's disease Curcumin glucoside |
| Subjects: | 600 Technology > 01 Medical sciences > 02 Anatomy 500 Natural Sciences and Mathematics > 04 Chemistry and Allied Sciences > 33 Terpenoids Chemistry |
| Divisions: | Dept. of Biochemistry |
| Depositing User: | Food Sci. & Technol. Information Services |
| Date Deposited: | 30 Jul 2008 09:34 |
| Last Modified: | 11 May 2012 03:50 |
| URI: | http://ir.cftri.res.in/id/eprint/8642 |
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