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Fibrillogenesis of Huntingtin and Other Glutamine Containing Proteins

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Protein Aggregation and Fibrillogenesis in Cerebral and Systemic Amyloid Disease

Part of the book series: Subcellular Biochemistry ((SCBI,volume 65))

Abstract

This chapter focuses on the aggregation of glutamine containing peptides and proteins with an emphasis on huntingtin protein, whose aggregation leads to the development of Huntington’s disease. The kinetics that leads to the formation of amyloids, the structure of aggregates of various types and the morphological mechanical properties of amyloid fibrils are described. The kinetics of amyloid fibril formation has been proposed to follow a nucleation dependent polymerization model, dependent upon the size of the nucleus. This model and the effect of the polyglutamine length on the nucleus size are reviewed. Aggregate structure is characterized at two different levels. The atomic-scale resolution structure of fibrillar and crystalline aggregates of polyglutamine containing proteins and peptides was determined by X-ray crystallography and solid-state nuclear magnetic resonance (NMR). The chapter outlines the results obtained by both these techniques. Atomic force microscopy (AFM) was instrumental in elucidating the morphology of fibrils, their organization and assembly. The chapter also discusses the high stability of amyloid fibrils, including their mechanical properties as revealed by AFM.

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Abbreviations

Htt:

Huntingtin protein

Aβ:

Amyloid-beta

AFM:

Atomic Force Microscopy

NMR:

Nuclear magnetic resonance

EPR:

Electron paramagnetic resonance

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Acknowledgements

The work was supported by National Institutes of Health Grants (1P01GM091743–01A1 and 1 R01 GM096039-01A1), U.S. Department of Energy Grant DE-FG02-08ER64579, National Science Foundation (EPS—1004094) and the Nebraska Research Initiative grant to Y.L.L.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Nanoimaging Core Facility College of Pharmacy, University of Nebraska Medical Center, COP 1012, 986025 Nebraska Medical Center, 68198-6025, Omaha, NE, USA

    Yuri L. Lyubchenko, Alexey V. Krasnoslobodtsev & Sorin Luca

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  1. Yuri L. Lyubchenko
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  2. Alexey V. Krasnoslobodtsev
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  3. Sorin Luca
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Correspondence to Yuri L. Lyubchenko .

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  1. Inst. of Zoology, University of Mainz, Becherweg 6, Mainz, 55099, Germany

    J. Robin Harris

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Lyubchenko, Y., Krasnoslobodtsev, A., Luca, S. (2012). Fibrillogenesis of Huntingtin and Other Glutamine Containing Proteins. In: Harris, J. (eds) Protein Aggregation and Fibrillogenesis in Cerebral and Systemic Amyloid Disease. Subcellular Biochemistry, vol 65. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5416-4_10

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