Cellular polyamines condense hyperphosphorylated Tau, triggering Alzheimer's disease

被引：17

作者：

Ivanov, Stefan M. ^{[1
,2
]}

Atanasova, Mariyana ^{[1
]}

Dimitrov, Ivan ^{[1
]}

Doytchinova, Irini A. ^{[1
]}

机构：

[1] Med Univ Sofia, Fac Pharm, Dunav 2 St, Sofia 1000, Bulgaria

[2] Univ Maryland, Inst Biosci & Biotechnol Res, Rockville, MD 20850 USA

来源：

SCIENTIFIC REPORTS | 2020年 / 10卷 / 01期

关键词：

LIQUID PHASE-SEPARATION; NEUROFIBRILLARY TANGLES; MOLECULAR-DYNAMICS; PROTEIN-TAU; PARKINSONS-DISEASE; HEPARAN-SULFATE; AGGREGATION; SPERMINE; PLAQUES; PERSPECTIVE;

D O I：

10.1038/s41598-020-67119-x

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Many gaps in our understanding of Alzheimer's disease remain despite intense research efforts. One such prominent gap is the mechanism of Tau condensation and fibrillization. One viewpoint is that positively charged Tau is condensed by cytosolic polyanions. However, this hypothesis is likely based on an overestimation of the abundance and stability of cytosolic polyanions and an underestimation of crucial intracellular constituents - the cationic polyamines. Here, we propose an alternative mechanism grounded in cellular biology. We describe extensive molecular dynamics simulations and analysis on physiologically relevant model systems, which suggest that it is not positively charged, unmodified Tau that is condensed by cytosolic polyanions but negatively charged, hyperphosphorylated Tau that is condensed by cytosolic polycations. Our work has broad implications for anti-Alzheimer's research and drug development and the broader field of tauopathies in general, potentially paving the way to future etiologic therapies.

引用

页数：13

共 91 条

[21] Glycogen synthase kinase-3 is associated with neuronal and glial hyperphosphorylated tau deposits in Alzheimer's disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration [J].