Mechanistic insights into the protective roles of polyphosphate against amyloid cytotoxicity

• Published in: Life science alliance 2019-10, Vol.2 (5), p.e201900486
• Main Authors: Lempart, Justine, Tse, Eric, Lauer, James A, Ivanova, Magdalena I, Sutter, Alexandra, Yoo, Nicholas, Huettemann, Philipp, Southworth, Daniel, Jakob, Ursula
• Format: Article
• Language: English
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.201900486

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.