[Role of Molecular Chaperones in Alzheimer's Disease]

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ACKNOWLEDGEMENT

I would take this opportunity to thank my research supervisor, family and friends for their support and guidance without which this research would not have been possible.

DECLARATION

I, [type your full first names and surname here], declare that the contents of this dissertation/thesis represent my own unaided work, and that the dissertation/thesis has not previously been submitted for academic examination towards any qualification. Furthermore, it represents my own opinions and not necessarily those of the University.

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TABLE OF CONTENTS

ACKNOWLEDGEMENTII

DECLARATIONIII

CHAPTER 1: MOLECULAR CHAPERONES1

Introduction1

Discovery3

Chaperonins3

Hsps5

CHAPTER 2: TYPES OF MOLECULAR CHAPERONES8

Enzymes that Assist in Protein Folding13

Protein Chaperones19

Mechanism of Action of Protein Chaperones27

CHAPTER 3: USE OF MOLECULAR CHAPERONES IN MEDICINE33

Use of Chaperones33

In Parkinson's Disease35

Huntington's disease37

CHAPTER 4: ALZHIEMER'S DISEASE39

General characteristics42

Prevalence43

Neuropathology44

Inheritance and Population Genetics46

Gene mutations and susceptibility genes related to Alzheimer disease48

Susceptibility genes49

Emerging genes51

Alpha-2 macroglobulin (A2M)52

Low-density lipoprotein receptor-related protein (LRP1)52

Interleukin-1 (IL-1)53

Symptoms54

Treatment56

CHAPTER 5: ROLE OF CHAPERONES IN CAUSING AND TREATING ALZHIEMER'S58

E3s and tauopathy60

Conclusion63

REFERENCES65

CHAPTER 1: MOLECULAR CHAPERONES

Introduction

Molecular chaperones are proteins and protein complexes that bind to misfolded or unfolded polypeptide chains and affect the subsequent folding processes of these chains. All proteins are created at the ribosome as straight chains of amino acids, but must be folded into a precise, three-dimensional shape (conformation) in order to perform their specific functions. The misfolded or unfolded polypeptide chains to which chaperones bind are said to be "non-native," meaning that they are not folded into their functional conformation. Chaperones are found in all types of cells and cellular compartments, and have a wide range of binding specificities and functional roles (Zimmerman, 2003).

Careful study, both in vivo and in the test tube, has demonstrated that molecular chaperones bind to their non-native substrate proteins by recognizing exposed non-polar surfaces ("non-polar" means that they are not attracted to water). In correctly folded proteins, these surfaces are usually buried away from the watery environment surrounding the protein. Chaperones promote correct folding of their substrate proteins by unfolding incorrect polypeptide chain conformations, and, in some cases, by providing a sequestered environment in which correct protein folding can occur. The activity of chaperones often requires the binding and hydrolysis of adenosine triphosphate (ATP).

Although only 20 to 30 percent of polypeptide chains require the assistance of a chaperone for correct folding under normal growth conditions, molecular chaperones are absolutely required for cell viability.

These molecules are proteins helping non-covalently in the assembly and folding of a protein during translation without forming part of its final assembly. Preventing non-productive protein-protein interactions and premature attainment of mature protein conformation, they can enable a protein to pass through a membrane (pore) in open conformation. One class of chaperones is the heat-shock proteins (prokaryotic and eukaryotic types occur) whose synthesis and/or activity rate is increased when the cell is subjected to higher-than-optimal temperatures (the appropriate enhancer is sometimes itself heat-affected, but heat-induced phosphorylation may be a factor).

Figure 1: Chaperones use energy from ATP to help misfolded proteins refold properly.

They are also implicated in ATP-driven protein transport across (e.g. mitochondrial) membranes, which involve temporary loss ...