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RNA Binds to Tau Fibrils and Sustains Template-Assisted Growth.

Dinkel PD, Holden MR, Matin N, Margittai M - Biochemistry (2015)

Bottom Line: These structural features are similar to those previously observed for heparin-induced fibrils, indicating that basic conformational properties are conserved, despite their being molecular differences of the nucleating agents.Furthermore, RNA sustains template-assisted growth and binds to the fibril surface and can be exchanged by heparin.These findings suggest that, in addition to mediating fibrillization, cofactors decorating the surface of Tau fibrils may modulate biological interactions and thereby influence the spreading of Tau pathology in the human brain.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208, United States.

ABSTRACT
Tau fibrils are the main proteinacious components of neurofibrillary lesions in Alzheimer disease. Although RNA molecules are sequestered into these lesions, their relationship to Tau fibrils is only poorly understood. Such understanding, however, is important, as short fibrils can transfer between neurons and nonproteinacious factors including RNA could play a defining role in modulating the latter process. Here, we used sedimentation assays combined with electron paramagnetic resonance (EPR), fluorescence, and absorbance spectroscopy to determine the effects of RNA on Tau fibril structure and growth. We observe that, in the presence of RNA, three-repeat (3R) and four-repeat (4R) Tau form fibrils with parallel, in-register arrangement of β-strands and exhibit an asymmetric seeding barrier in which 4R Tau grows onto 3R Tau seeds but not vice versa. These structural features are similar to those previously observed for heparin-induced fibrils, indicating that basic conformational properties are conserved, despite their being molecular differences of the nucleating agents. Furthermore, RNA sustains template-assisted growth and binds to the fibril surface and can be exchanged by heparin. These findings suggest that, in addition to mediating fibrillization, cofactors decorating the surface of Tau fibrils may modulate biological interactions and thereby influence the spreading of Tau pathology in the human brain.

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Related in: MedlinePlus

Schematic modelfor cofactor participation in Tau fibril growthand decoration. RNA (blue) not only sustains template-assisted growthbut also decorates the fibril surface. Heparin (red) can substituteRNA on the surface and thereby change the properties of the fibril.Different conformers of Tau fibrils (squares, triangles, and hexagons)will have distinct associations. The decoration of Tau fibrils withother cofactors (not shown) could produce a complex structural ensemblewith diverse biological activities.
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fig7: Schematic modelfor cofactor participation in Tau fibril growthand decoration. RNA (blue) not only sustains template-assisted growthbut also decorates the fibril surface. Heparin (red) can substituteRNA on the surface and thereby change the properties of the fibril.Different conformers of Tau fibrils (squares, triangles, and hexagons)will have distinct associations. The decoration of Tau fibrils withother cofactors (not shown) could produce a complex structural ensemblewith diverse biological activities.

Mentions: Regardless of the stabilizing role ofcofactors, the decorationof Tau fibrils with nonproteinacious molecules could encode importantbiological information. The nature of the cofactor on the surfaceof the fibril could influence how the fibril interacts with cellularcomponents. The uptake of Tau fibrils, for example, is, at least inpart, mediated by heparan sulfate proteoglycans (HSPGs).57 The efficiency of this process could dependon the accessibility of binding sites and the particular nature ofthe cofactors that decorate the fibril. We observed that heparin replacesRNA on the fibril surface. A similar mechanism could facilitate fibrilbinding to HSPGs on the cell surface. Exchangeable cofactors on thesurface of Tau fibrils may enhance fibril transmission between neurons,whereas nonexchangeable ones may inhibit it. A new intricate modelemerges in which cofactors not only sustain template-assisted growthbut also are part of the fibril structure (Figure 7). In some fibrils, cofactors may be notonly bound to the surface but also incorporated into the amyloidogeniccore. The K19 fibrils that were characterized in this study may beone example. In these fibrils, a significant population of RNA moleculescould not be replaced by heparin (Figures 5 and 6).


RNA Binds to Tau Fibrils and Sustains Template-Assisted Growth.

Dinkel PD, Holden MR, Matin N, Margittai M - Biochemistry (2015)

Schematic modelfor cofactor participation in Tau fibril growthand decoration. RNA (blue) not only sustains template-assisted growthbut also decorates the fibril surface. Heparin (red) can substituteRNA on the surface and thereby change the properties of the fibril.Different conformers of Tau fibrils (squares, triangles, and hexagons)will have distinct associations. The decoration of Tau fibrils withother cofactors (not shown) could produce a complex structural ensemblewith diverse biological activities.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4526887&req=5

fig7: Schematic modelfor cofactor participation in Tau fibril growthand decoration. RNA (blue) not only sustains template-assisted growthbut also decorates the fibril surface. Heparin (red) can substituteRNA on the surface and thereby change the properties of the fibril.Different conformers of Tau fibrils (squares, triangles, and hexagons)will have distinct associations. The decoration of Tau fibrils withother cofactors (not shown) could produce a complex structural ensemblewith diverse biological activities.
Mentions: Regardless of the stabilizing role ofcofactors, the decorationof Tau fibrils with nonproteinacious molecules could encode importantbiological information. The nature of the cofactor on the surfaceof the fibril could influence how the fibril interacts with cellularcomponents. The uptake of Tau fibrils, for example, is, at least inpart, mediated by heparan sulfate proteoglycans (HSPGs).57 The efficiency of this process could dependon the accessibility of binding sites and the particular nature ofthe cofactors that decorate the fibril. We observed that heparin replacesRNA on the fibril surface. A similar mechanism could facilitate fibrilbinding to HSPGs on the cell surface. Exchangeable cofactors on thesurface of Tau fibrils may enhance fibril transmission between neurons,whereas nonexchangeable ones may inhibit it. A new intricate modelemerges in which cofactors not only sustain template-assisted growthbut also are part of the fibril structure (Figure 7). In some fibrils, cofactors may be notonly bound to the surface but also incorporated into the amyloidogeniccore. The K19 fibrils that were characterized in this study may beone example. In these fibrils, a significant population of RNA moleculescould not be replaced by heparin (Figures 5 and 6).

Bottom Line: These structural features are similar to those previously observed for heparin-induced fibrils, indicating that basic conformational properties are conserved, despite their being molecular differences of the nucleating agents.Furthermore, RNA sustains template-assisted growth and binds to the fibril surface and can be exchanged by heparin.These findings suggest that, in addition to mediating fibrillization, cofactors decorating the surface of Tau fibrils may modulate biological interactions and thereby influence the spreading of Tau pathology in the human brain.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80208, United States.

ABSTRACT
Tau fibrils are the main proteinacious components of neurofibrillary lesions in Alzheimer disease. Although RNA molecules are sequestered into these lesions, their relationship to Tau fibrils is only poorly understood. Such understanding, however, is important, as short fibrils can transfer between neurons and nonproteinacious factors including RNA could play a defining role in modulating the latter process. Here, we used sedimentation assays combined with electron paramagnetic resonance (EPR), fluorescence, and absorbance spectroscopy to determine the effects of RNA on Tau fibril structure and growth. We observe that, in the presence of RNA, three-repeat (3R) and four-repeat (4R) Tau form fibrils with parallel, in-register arrangement of β-strands and exhibit an asymmetric seeding barrier in which 4R Tau grows onto 3R Tau seeds but not vice versa. These structural features are similar to those previously observed for heparin-induced fibrils, indicating that basic conformational properties are conserved, despite their being molecular differences of the nucleating agents. Furthermore, RNA sustains template-assisted growth and binds to the fibril surface and can be exchanged by heparin. These findings suggest that, in addition to mediating fibrillization, cofactors decorating the surface of Tau fibrils may modulate biological interactions and thereby influence the spreading of Tau pathology in the human brain.

Show MeSH
Related in: MedlinePlus