This project is about the mechanisms associated with amyloid induced cytotoxicity. Amyloidoses consist of several diseases where normal or mutated protein precipitates into amyloid fibrils. Dysfunction of organs and toxicity to nervous tissue is triggered by the deposition of fibrils. Presently 24 unique proteins and peptides are acknowledged to have the ability to form amyloid fibrils. One of the most popular are Amyloid beta peptide and Prione protein causing Alzheimer’s disease and Creutzfeld Jacob’s disease respectively. In this thesis we will look into the structural properties of cytotoxic amyloid and consider the mechanisms involved. The model protein mostly utilized in the research was the plasma protein transthyretin (TTR). Familial Amyloidotic Polyneuropathy (FAP) is a hereditary, autosomal-dominant neurodegenerative disease attributable to point mutations in the TTR gene. Probably the most common variants of FAP is a mutation in position 30 where alanine is swapped for methonine. TTR is released into the plasma as a tetramer. Point mutations destabilize the tetramer ultimately causing disassembled monomers that go through partial denaturation as an initiation step to aggregation and amyloid fibril formation. In vivo amyloidogenesis requires a long time and doesn’t occur until late in adult life.
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Contents
INTRODUCTION
AMYLOIDOSIS
Protein folding and misfolding
Common properties of amyloid fibrils
TRANSTHYRETIN (TTR)
Function and structure
TTR associated amyloidosis
Senile Systemic Amyloidosis (SSA)
Familial amyloidotic polyneuropathy (FAP)
Therapeutic strategies in amyloidosis
APOPTOSIS
Caspases
Caspase-independent apoptosis
Calcium (Ca2+)
Reactive oxygene species (RO
AIMS OF THIS THESIS
RESULTS AND DISCUSSION
TTR OLIGOMERS ARE TOXIC IN CONTRAST TO
MATURE FIBRILS (PAPER I)
THE TOXIC EFFECT OF EQUINE LYSOZYME (EL) IS
DEPENDENT OF THE SIZE OF OLIGOMERS (PAPER II)
AMYLOIDOGENIC TTR OUTSIDE THE SECRETORY
PATHWAY IS DEGRADED (PAPER III)
THE CYTOTOXIC EFFECT OF TTR OLIGOMERS IS
CASPASE-INDEPENDENT (PAPER IV)
CONCLUDING REMARKS……….
Source: Umea University
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