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Biophysical and biological properties of atypical sphingolipids : implications to physiology and pathophysiology
Publication . Da Cunha Branco Dos Santos, Tânia; Silva, Liana Casquinha da; Prieto, Manuel; Hornemann, Thorsten
1-deoxy-sphingolipids lack the C1-OH on their sphingoid base and present a cis ∆14-15 double bond instead of the canonical trans ∆4-5 double bond. Increased 1-deoxy-sphingolipid levels are directly correlated with the development and progression of hereditary sensory and autonomic neuropathy type 1 (HSAN1) and diabetes type 2. Different mechanisms have been proposed to explain the cytotoxicity of 1-deoxy-sphingolipids. However, these are highly dependent on the cell line studied and on the lipid concentration used, limiting the understanding of the mechanisms by which 1-deoxy-sphingolipids exert their patho-physiological roles. As for other sphingolipids, 1-deoxy-sphingolipids biological action might be related to the specific changes that each of the species cause on the biophysical properties of the membranes. Nonetheless, studies that comprehensively address the 1-deoxy-sphingolipids biophysical behavior are still scarce. Thereby, the goal of this study was to bring more insight into the biophysical impact of 1-deoxy-sphingolipids in both model and cellular membranes. Using complementary established fluorescence spectroscopy and microscopy methodologies and a multi-probe approach it was possible to conclude that: i) 1-deoxy-sphingolipids fail to form ordered domains as efficiently as canonical sphingolipids; ii) the presence, position and configuration of the sphingoid base double bond has a stronger influence on sphingolipids-induced changes on membrane biophysical properties than the structure of its C1 group; iii) external addition of 1-deoxy-sphingoid bases to living cells induce rapid changes in membrane fluidity in a sphingolipid structure dependent manner; iv) 1-deoxy-sphingolipids effects on membrane properties are specific and distinct from their canonical counterparts; v) endogenous elevation of 1-deoxy-sphingolipids due to mutations associated with HSAN1 development cause significant changes in the fluidity of cell membranes in a mutation dependent manner. Overall, the results suggest that pathologically elevated levels of 1-deoxy-sphingolipids compromise the biophysical properties of the membranes, which might impair proper cell functioning leading to the development of pathological conditions.
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Fundação para a Ciência e a Tecnologia
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3599-PPCDT
Número da atribuição
PTDC/BIA-BFS/29448/2017