Current Science

Open Access Open Access  Restricted Access Subscription Access

Computational Study of Intermolecular Interactions between α-Synuclein Fibrils and Tau Protein Propagating Tau Aggregation


Affiliations
1 Molecular Modelling and Simulation Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur 784 028, India
 

α-Synuclein is the principal component responsible for the onset of Parkinson's disease, a neurodegenerative disorder. It has been recently suggested that α-synuclein fibrils probably interact with Tau protein, inhibit its function to stabilize microtubules, and also promote Tau aggregation, leading to dysfunction of neuronal cells. Here, we have studied the interactions between α-synuclein fibrils and Tau protein. The results show that the basic region of Tau protein strongly interacts with the C-terminal acidic regions of α-synuclein fibrils, and undergoes conformational change resulting in the formation of seed for assembly of Tau into amyloid-like fibrils.

Keywords

Fibrils, Microtubules, Intermolecular Interactions, Neurodegenerative Disorders.
User
Notifications
Font Size

  • Polymeropoulos, M. H. et al., Mutation in the -synuclein gene identified in families with Parkinson’s disease. Science, 1997, 276, 2045–2047.

  • Kruger, R. et al., Ala30Pro mutation in the gene encoding α-synuclein in Parkinson’s disease. Nature Genet., 1998, 18, 106–108.

  • Zarranz, J. J. et al., The new mutation, E46K, of -synuclein causes Parkinson and Lewy body dementia. Ann. Neurol., 2004, 55, 164–173.

  • Appel-Cresswell, S. et al., α-Synucleinp.H50Q, a novel pathogenic mutation for Parkinson’s disease. Mov. Disord., 2013, 28, 811–813.

  • Lesage, S. et al. and French Parkinson’s Disease Study Group, G51D α-synuclein mutation causes a novel parkinsonianpyramidal syndrome. Ann. Neurol., 2013, 73, 459–471.

  • Pasanen, P. et al., Novel -synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson’s diseasetype pathology. Neurobiol. Aging, 2014, 35, 2180.

  • Spillantini, M. G., Schmidt, M. L., Lee, V. M., Trojanowski, J. Q., Jakes, R. and Goedert, M., Alpha-synuclein in Lewy bodies. Nature, 1997, 388, 839–840.

  • Spillantini, M. G., Crowther, R. A., Jakes, R., Cairns, N. J., Lantos, P. L. and Goedert, M., Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci. Lett., 1998, 251, 205–208.

  • Wakabayashi, K., Hayashi, S., Kakita, A., Yamada, M., Toyoshima, Y., Yoshimoto, M. and Takahashi, H., Accumulation of synuclein/NACP is a cytopathological feature common to Lewy body disease and multiple system atrophy. Acta Neuropathol., 1998, 96, 445–452.

  • Maroteaux, L., Campanelli, J. T. and Scheller, R. H., Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J. Neurosci., 1988, 8, 2804–2815.

  • Crowther, R. A., Jakes, R., Spillantini, M. G. and Goedert, M., Synthetic filaments assembled from C-terminally truncated α-synuclein. FEBS Lett., 1998, 436, 309–312.

  • Serpell, L. C., Berriman, J., Jakes, R., Goedert, M. and Crowther, R. A., Fiber diffraction of synthetic α-synuclein filaments shows amyloidlike cross-conformation. Proc. Natl. Acad. Sci. USA, 2000, 97, 4897–4902.

  • Alim, M. A. et al., Demonstration of a role for -synuclein as a functional microtubule-associated protein. J. Alzheimers Dis., 2004, 6, 435–442.

  • Nonaka, T., Watanabe, S. T., Iwatsubo, T. and Hasegawa, M., Seeded aggregation and toxicity of α-synuclein and π cellular models of neurodegenerative diseases. J. Biol. Chem., 2010, 285, 34885–34898.

  • Oikawa, T., Nonaka, T., Terada, M., Tamaoka, A., Hisanaga, S. and Hasegawa, M., α-Synuclein fibrils exhibit gain of toxic function, promoting tau aggregation and inhibiting microtubule assembly. J. Biol. Chem., 2016, 291, 15046–15056.

  • Giasson, B. I. et al., Initiation and synergistic fibrillization of π and α-synuclein. Science, 2003, 300, 636–640.

  • Waxman, E. A. and Giasson, B. I., Induction of intracellular π aggregation is promoted by α-synuclein seeds and provides novel insights into the hyperphosphorylation of π. J. Neurosci., 2011, 31, 7604–7618.

  • Masuda, M. et al., Small molecule inhibitors of -synuclein filament assembly. Biochemistry, 2006, 45, 6085–6094.

  • Lee, H. J., Khoshaghideh, F., Patel, S. and Lee, S. J., Clearance of α-synuclein oligomeric intermediates via the lysosomal degradation pathway. J. Neurosci., 2004, 24, 1888–1896.

  • Conway, K. A., Harper, J. D. and Lansbury, P. T., Accelerated in vitro fibril formation by a mutant -synuclein linked to earlyonset Parkinson disease. Nature Med., 1998, 4, 1318–1320.

  • Choi, W. et al., Mutation E46K increases phospholipid binding and assembly into filaments of human α-synuclein. FEBS Lett., 2004, 576, 363–368.

  • Conway, K. A., Lee, S. J., Rochet, J. C., Ding, T. T., Harper, J. D., Williamson, R. E. and Lansbury Jr, P. T., Accelerated oligomerization by Parkinson’s disease linked α-synuclein mutants. Ann. NY Acad. Sci., 2000, 920, 42–45.

  • Yonetani, M., Nonaka, T., Masuda, M., Inukai, Y., Oikawa, T., Hisanaga, S. and Hasegawa, M., Conversion of wild-type α-synuclein into mutant-type fibrils and its propagation in the presence of A30P mutant. J. Biol. Chem., 2009, 284, 7940–7950.

  • Laskowski, R. A., PDBsum: summaries and analyses of PDB structures. Nucleic Acids Res., 2001, 29, 221–222.

  • Tuttle, M. D. et al., Solid-state NMR structure of a pathogenic fibril of full-length human alpha-synuclein. Nature Struct. Mol. Biol., 2016, 23, 409–415.

  • Berman, H. M. et al., The Protein Data Bank. Nucleic Acids Res., 2000, 28, 235–242.

  • Zhang, Y., I-TASSER server for protein 3D structure prediction. BMC Bioinformatics, 2008, 9, 40.

  • Duhovny, D., Nussinov, R. and Wolfson, H. J., Efficient Unbound Docking of Rigid Molecules, Springer-Verlag, Berlin, 2002, pp. 185–200.

  • Zhang, C., Vasmatzis, G., Cornette, J. L. and DeLisi, C., Determination of atomic desolvation energies from the structures of crystallized proteins. J. Mol. Biol., 1997, 267, 707–726.

  • Andrusier, N., Nussinov, R. and Wolfson, H. J., FireDock: fast interaction refinement in molecular docking. Proteins, 2007, 69, 139–159.

  • Kingsford, C. L., Chazelle, B. and Singh, M., Solving and analyzing side chain positioning problems using linear and integer programming. Bioinformatics, 2005, 21, 1028–1036.

  • Krieger, E., Koraimann, G. and Vriend, G., Increasing the precision of comparative models with YASARA NOVA – a selfparameterizing force field. Proteins, 2002, 47, 393–402.


Abstract Views: 241

PDF Views: 76




  • Computational Study of Intermolecular Interactions between α-Synuclein Fibrils and Tau Protein Propagating Tau Aggregation

Abstract Views: 241  |  PDF Views: 76

Authors

Airy Sanjeev
Molecular Modelling and Simulation Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur 784 028, India
Venkata Satish Kumar Mattaparthi
Molecular Modelling and Simulation Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur 784 028, India

Abstract


α-Synuclein is the principal component responsible for the onset of Parkinson's disease, a neurodegenerative disorder. It has been recently suggested that α-synuclein fibrils probably interact with Tau protein, inhibit its function to stabilize microtubules, and also promote Tau aggregation, leading to dysfunction of neuronal cells. Here, we have studied the interactions between α-synuclein fibrils and Tau protein. The results show that the basic region of Tau protein strongly interacts with the C-terminal acidic regions of α-synuclein fibrils, and undergoes conformational change resulting in the formation of seed for assembly of Tau into amyloid-like fibrils.

Keywords


Fibrils, Microtubules, Intermolecular Interactions, Neurodegenerative Disorders.

References





DOI: https://doi.org/10.18520/cs%2Fv112%2Fi11%2F2219-2225