Modulating the aggregation of alpha-synuclein and prion protein with small molecules.
by Luis Eduardo Fonseca Ornelas
Date of Examination:2016-02-14
Date of issue:2016-11-07
Advisor:Prof. Dr. Markus Zweckstetter
Referee:Prof. Dr. Tiago Fleming Outeiro
Referee:Prof. Dr. Henning Urlaub
Referee:Prof. Dr. Kai Tittmann
Referee:Prof. Dr. Christian Griesinger
Referee:Prof. Dr. Reinhard Jahn
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Name:PhD thesis Fonseca-Ornelas.pdf
EnglishAs living and health conditions improve in modern societies, the percentage of older people rises. A byproduct of this ageing is the marked increase of cases of cancer, cardiovascular, and neurodegenerative diseases. Many neurodegenerative diseases share a common hallmark: Protein misfolding and aggregation that either drives or accompanies neuronal death in discrete or widespread brain regions. Finding ways to inhibit protein aggregation is thus a key step in preventing neurodegenerative diseases. Out of these, Parkinson’s disease (PD) is the second most common disorder, affecting more than five million people worldwide. Its most common symptoms include slowness of movement, rigidity, resting tremor, and postural instability. At the tissue level, PD is characterized by a profound loss of dopaminergic neurons in the substantia nigra of the brain. This loss generates a lack of dopamine in the striatum and a concomitant deregulation of the limbic system that causes the main symptoms in PD patients. Closer examination of the substantia nigra reveals the formation of protein aggregates in which the main component is a misfolded form of the protein alpha-synuclein. This, together with the fact that triplications and point mutations in the alpha-synuclein gene are associated with familial forms of PD makes alpha-synuclein an optimal target for research. As part of this work we have now discovered that the first steps of alpha-synuclein aggregation follow significantly different pathways in a lipid-based environment versus aggregation in solution, and that different small chemical compounds display distinct anti-aggregation properties depending on the presence or absence of lipid vesicles. We further demonstrated that the aggregation of vesicle-bound alpha-synuclein depends on the insertion of the hydrophobic domain into the membrane. The insertion of alpha-synculein into the membrane can be prevented by a small chemical compound, opening a novel approach to block aggregation and toxicity of alpha-synuclein. The second part of my thesis revolves around the aggregation properties of a small peptide from the prion protein (PrP). We have shown that the residue at position 129 plays a central role in its aggregation and that a region spanning from residues 111-137 form a strongly solvent-protected segment, with residues 111 and 135 being in close spatial proximity. We have also demonstrated that the protonation state of a histidine residue in position 111 critically impacts the aggregation of this prion peptide. Furthermore, we showed that sequence homology within the solvent-protected region is of utmost importance for the height of the species barrier, a central aspect of PrP biology.
Keywords: Parkinson's disease; alpha-synuclein; NMR; aggregation