TY - JOUR T1 - Mechanistic insights into the protective roles of polyphosphate against amyloid cytotoxicity JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201900486 VL - 2 IS - 5 SP - e201900486 AU - Justine Lempart AU - Eric Tse AU - James A Lauer AU - Magdalena I Ivanova AU - Alexandra Sutter AU - Nicholas Yoo AU - Philipp Huettemann AU - Daniel Southworth AU - Ursula Jakob Y1 - 2019/10/01 UR - https://www.life-science-alliance.org/content/2/5/e201900486.abstract N2 - 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. ER -