Protein-lipid interactions in molecular pathways of Parkinson’s and Alzheimer’s diseases

Alzheimer’s and Parkinson’s (AD and PD) diseases, increasingly prevalent and currently incurable neurodegenerative disorders, are characterised by the accumulation of proteinaceous pathogenic inclusions in the central nervous system. The key proteins involved in the pathogenesis of AD and PD are amyloid β 1–42 (Aβ42) and α-synuclein (αS), which cause the toxicity in AD and PD through aberrant interactions with lipid membranes. Despite current significant effort, the link between αS-/Aβ42-membrane interactions and disease mechanisms remains elusive. In this work, I applied a set of bulk and microfluidic assays to address this problem by quantifying misfolded αS- and Aβ42-lipid membrane interactions. In the initial section of the thesis, I present the results of a study that delves into the interactions between oligomeric/monomeric αS and lipid membranes. The findings revealed striking differences in membrane binding affinity of the two species. Furthermore, misfolded oligomeric αS competes with monomeric αS for membrane binding, displacing the latter. Prompted by these findings, I investigated the possible mechanisms preventing aberrant aggregated αS-membrane binding. Results indicate that βS, a homologous protein from the synuclein family, can displace aggregated αS from lipid surfaces and mitigate compromised membrane integrity. The final sections of the thesis focus on AD-linked Aβ42 aggregation kinetics and mechanisms on lipid membranes. By applying chemical kinetics approach, I found that rates of distinct microscopic Aβ42 aggregation steps depend on the composition of cell membrane mimetic liposomes. Furthermore, the results show that lipid surfaces trigger Aβ42 primary nucleation by promoting liquid-liquid phase separation, which is an intermediate state in the amyloid cascade. These fundamental findings enhance the understanding of lipid-mediated molecular pathways in AD and PD, and provide insights that pave the way for future exploration of neurodegenerative disease pathology.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Šneiderienė, Greta

Advisor dc:contributor.advisor

• Knowles, Tuomas

• alpha-synuclein
• Alzheimer's disease
• Amyloid beta 42
• Parkinson's disease
• Protein aggregation
• protein-lipid interactions

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/cd6737cd-3eba-4cf2-991e-bfc52bf5e905/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

Author Identifier

0000-0002-4585-5091

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/375423