PT  - JOURNAL ARTICLE
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
TI  - Mechanistic insights into the protective roles of polyphosphate against amyloid cytotoxicity
AID  - 10.26508/lsa.201900486
DP  - 2019 Oct 01
TA  - Life Science Alliance
PG  - e201900486
VI  - 2
IP  - 5
4099  - https://www.life-science-alliance.org/content/2/5/e201900486.short
4100  - https://www.life-science-alliance.org/content/2/5/e201900486.full
SO  - Life Sci. Alliance2019 Oct 01; 2
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.