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- W3003579569 abstract "Aggregation and deposition of disease-associated protein is a pathological hallmark of several human disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). These diseases are characterized by the formation of amyloid-β (Aβ) and α-synuclein (α-syn) amyloid fibrils, in extracellular and intracellular locations, respectively. Prior to extracellular deposition of Aβ into plaques, Aβ also accumulates within neurons, but the molecular and cellular mechanisms contributing to uptake are not fully understood. Moreover, exact links between disease onset and progression are missing, hindering the development of new disease-modifying therapies. This Thesis describes my research to elucidate how chemical and physical characteristics of Aβ and α-syn, and their ensuing aggregates, influence their cellular uptake. This is important as the endolysosomal system has been implicated as a potential site for onset and progression of disease pathology. Focusing on Aβ uptake I demonstrate that the most aggregation-prone and neurotoxic variant Aβ(1-42) is endocytosed twice as efficiently as Aβ(1-40). I show that the uptake of both variants occurs via clathrin- and dynamin-independent endocytosis, but my work also points to a mechanistic difference; Aβ(1-42) is for example more sensitive to inhibitors of action polymerisation. Further, in studies of Aβ(1-42), I demonstrate that uptake is regulated by small Rho GTPases and highly sensitive to changes in membrane tension, but apparently not via GRAF1-regulated CLIC/GEECs, suggesting the involvement of yet unidentified molecular players. I also show how uptake of pre-formed α-syn fibrils is inversely related to fibril length, and correlates to reductions in metabolic activity, pointing to an important role of cellular uptake and endolysosomal accumulation in toxicity. Lastly, I demonstrate that both monomeric Aβ and fibrillar α-syn are dependent on cell surface proteoglycans for uptake. Importantly, I show that for Aβ this dependency builds up over time, suggesting that local peptide aggregation at the cell surface could precede uptake. Altogether, this Thesis contribute new molecular and mechanistic insights into how cellular uptake contributes to intraneuronal accumulation of amyloidogenic proteins relevant in neurodegenerative disease." @default.
- W3003579569 created "2020-02-07" @default.
- W3003579569 creator A5079838928 @default.
- W3003579569 date "2020-01-01" @default.
- W3003579569 modified "2023-09-27" @default.
- W3003579569 title "Cellular Uptake of Amyloid Forming Proteins Related to Neurodegenerative Disease" @default.
- W3003579569 hasPublicationYear "2020" @default.
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