%0 Journal Article %A Justine Lempart %A Eric Tse %A James A Lauer %A Magdalena I Ivanova %A Alexandra Sutter %A Nicholas Yoo %A Philipp Huettemann %A Daniel Southworth %A Ursula Jakob %T Mechanistic insights into the protective roles of polyphosphate against amyloid cytotoxicity %D 2019 %R 10.26508/lsa.201900486 %J Life Science Alliance %P e201900486 %V 2 %N 5 %X The universally abundant polyphosphate (polyP) accelerates fibril formation of disease-related amyloids and protects against amyloid cytotoxicity. To gain insights into the mechanism(s) by which polyP exerts these effects, we focused on α-synuclein, a well-studied amyloid protein, which constitutes the major component of Lewy bodies found in Parkinson’s disease. Here, we demonstrate that polyP is unable to accelerate the rate-limiting step of α-synuclein fibril formation but effectively nucleates fibril assembly once α-synuclein oligomers are formed. Binding of polyP to α-synuclein either during fibril formation or upon fibril maturation substantially alters fibril morphology and effectively reduces the ability of α-synuclein fibrils to interact with cell membranes. The effect of polyP appears to be α-synuclein fibril specific and successfully prevents the uptake of fibrils into neuronal cells. These results suggest that altering the polyP levels in the extracellular space might be a potential therapeutic strategy to prevent the spreading of the disease. %U https://www.life-science-alliance.org/content/lsa/2/5/e201900486.full.pdf