RT Journal Article
SR Electronic
T1 Mechanistic Insights into the Protective Roles of Polyphosphate Against Amyloid Cytotoxicity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 704882
DO 10.1101/704882
A1 Justine Lempart
A1 Eric Tse
A1 James A. Lauer
A1 Magdalena I Ivanova
A1 Alexandra Sutter
A1 Nicholas Yoo
A1 Philipp Huettemann
A1 Daniel Southworth
A1 Ursula Jakob
YR 2019
UL http://biorxiv.org/content/early/2019/07/16/704882.abstract
AB 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.