Interactions of Alpha Synuclein and Tau in Neurodegenerative Diseases

Key proteins implicated in neurodegenerative diseases are alpha synuclein and tau. Tau aggregation into neurofibrillary tangles, along with amyloid-beta aggregation into plaques, is a hallmark of Alzheimer’s Disease (AD) and alpha synuclein aggregation into Lewy bodies is a pathological hallmark of Parkinson’s Disease (PD). 

Yet, “tauopathies” and “synucleinopathies” frequently share features, and tau and alpha synuclein can interact in ways that promote the other’s aggregation.

Alpha Synuclein in Alzheimer’s Disease

Typically, AD is characterized by tau neurofibrillary tangles and amyloid-beta plaques. Though, over half of AD patients’ brains were seen to also contain Lewy bodies1 and high levels of alpha synuclein were found in AD patients’ cerebrospinal fluid (CSF).2

The role of Lewy bodies and alpha synuclein in AD is not well-understood. Lewy bodies are also able to exist in the brains of healthy subjects3 and it is possible they are neuroprotective or presymptomatic.4

It is possible that the misfolding of aggregation-prone proteins such as alpha synuclein is a downstream effect of disease progression, since AD involves disruption of protein homeostasis.5

Tau in Parkinson’s Disease

Neurofibrillary tangles can happen in sporadic PD6 and in Parkinson’s Disease Dementia (PDD).7

Alpha Synuclein and Tau Colocalization

It has been found that Lewy bodies and tangles do not co-occur by chance, but because alpha synuclein and tau, and amyloid-beta promote each other’s aggregation.10,11 Not only can Lewy bodies and neurofibrillary tangles coexist in the same disease state, but tau and alpha synuclein can also colocalize within these aggregates.8,9

How do Alpha Synuclein and Tau Interact?

Alpha synuclein can encourage tau oligomerization12 and fibrillization.10 Although, tau can induce alpha synuclein aggregation.11,12 This can be seen in vitro and in mouse models – transgenic mice which are utilized to model advanced AD, developed alpha synuclein inclusions despite not possessing an alpha synuclein transgene.15

In neurotoxin-induced16 and alpha synuclein overexpression mouse models of PD17, increased amounts of phosphorylated tau have also been observed.

How does Alpha Synuclein Promote Tau Aggregation?

By reducing tau’s ability to stabilize microtubules, alpha synuclein is thought to trigger tauopathies.18 As it is thought to form a complex with tau and alpha synuclein, which then leads to tau phosphorylation, GSK3β may mediate this process.18

The positively-charged central region of tau is thought to interact electrostatically with the negatively charged C-terminal region of alpha synuclein, which could disrupt the interactions between microtubules and tau.14

How does Tau Promote Alpha Synuclein Aggregation?

Interestingly, it has been demonstrated that tau overexpression has increased the amount of alpha synuclein aggregates but decreased their size.13 Since smaller fibrils are thought to be more toxic, this may account for enhanced alpha synuclein toxicity.

The positively charged tau is thought to disrupt repulsive interactions between alpha synuclein proteins, which would heighten aggregation.14 It should be noted that amyloid-beta is also likely to be involved in these processes, as it interacts with both tau and alpha synuclein.

StressMarq supplies a number of alpha synuclein and tau fibrillized proteins and antibodies for use in neurodegeneration research.

References and Further Reading

  1. Hamilton, R.L. “Lewy bodies in Alzheimer’s disease: a neuropathological review of 145 cases using alpha-synuclein immunohistochemistry.” Brain Pathology 2000, 10(3):378-84.
  2. Slaets, S. et al. “Increased CSF α-synuclein levels in Alzheimer’s disease: Correlation with tau levels.” Alzheimer’s and Dementia 2014, 10(5):S290-S298.
  3. Jellinger, K.A. “Lewy body-related alpha-synucleinopathy in the aged human brain.” J Neural Transm (Vienna) 2004, 111(10-11):1219-1235.
  4. Wakabayashi, K. “Lewy body formation in Parkinson’s disease: neurodegeneration or neuroprotection?” Rinsho Shinkeigaku 2008, 48(11):981-983.
  5. Kikis, E.A, Gidalevitz, T., Morimoto, R.I. “Protein homeostasis in models of aging and age-related conformational disease.” Adv Exp Med Biol 2010, 964:138-159.
  6. Joachim, D.L., Morris, J.H., Kosik., K.S., Selkoe, D.J. “Tau antisera recognize neurofibrillary tangles in a range of neurodegenerative disorders.” Ann Neurol 1987, 22:514-520.
  7. Irwin, D.J., Lee, V.M.-Y., Trojanowski, J.Q. “Parkinson’s disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies.” Nat Rev Neurosci 2013, 14(9):626-636.
  8. Ishizawa, T., Mattila, P., Davies, P., Wang, D., Dickson, D.W. “Colocalization of tau and alpha-synuclein epitopes in Lewy bodies.” J Neuropathol Exp Neurol 2003, 62:389-397.
  9. Fujishiro, H., Tsuboi, Y., Lin, W.-L., Uchikado, H., Dickson, D.W. “Co-localization of tau and α-synuclein in the olfactory bulb in Alzheimer’s disease with amygdala Lewy bodies.” Acta Neuropathol 2008, 116(1):17-24.
  10. Giasson, Bl., Forman, M.S., Higuchi, M., Golbe, L.I., Graves, C.L., Kotzbauer, P.T., Trojanowski, J.Q., Lee, V.M. “Initiation and synergistic fibrillization of tau and alpha-synuclein.” Science 2003, 300(5619):636-40.
  11. Lee, V.M., Giasson, B.I., Trojanowski, J.Q. “More than just two peas in a pod: common amyloidogenic properties of tau and alpha-synuclein in neurodegenerative diseases.” Trends Neurosci, 2004, 27(3):129-34.
  12. Castillo-Carranza, D.L, Guerrero-Munoz, M.J., Sengupta, U., Gerson, J.E., Kayed, R. “α-Synuclein Oligomers Induce a Unique Toxic Tau Strain.” Biological Psychiatry 2018, 84:466-508.
  13. Badiola, N., de Oliveira, R.M., Herrera, F., Guardia-Laguarta, C., Goncalves, S.A., Pera, M., Suarez-Calvet, M., Clarimon, J., Outeiro, T.F., Lleo, A. “Tau Enhances α-Synuclein Aggregation and Toxicity in Cellular Models of Synucleinopathy.” PLoS ONE 6(10): e26609.
  14. Dasari, A.K.R., Kayed, R., Wi, S., Lim., K.H. “Tau Interacts with the C-Terminal Region of α‑Synuclein, Promoting Formation of Toxic Aggregates with Distinct Molecular Conformations.” Biochemistry 2019, 58:2814-2821.
  15. Chen, W. “Studying the Interactions Between Tau, Amyloid, and α-Synuclein in Alzheimer’s Disease Animal and Human Cell Models.” UC Irvine Electronic Theses and Dissertations
  16. Duka, T., Rusnak, M., Drolet, R.E., Duka, V., Wersinger, C., Goudreau, J.L., Sidhu, A. “Alpha-synuclein induces hyperphosphorylation of Tau in the MPTP model of parkinsonism.” Faseb J 2006, 20:2302–2312.
  17. Haggerty, T., Credle, J., Rodriguez, O., Wills, J., Oaks, A.W., Masliah, E., Sidhu, A. “Hyperphosphorylated Tau in an α-synuclein overexpressing transgenic model of Parkinson’s disease.” Eur J Neurosci 2011, 33(9):1598-1610.
  18. Carnwath, T., Mohammed, R., Tsiang, D. “The direct and indirect effects of α-synuclein on microtubule stability in the pathogenesis of Parkinson’s disease.” Neuropsychiatr Dis Treat 2018, 14:1685-1695.

Acknowledgments

Produced from materials originally authored by Patricia Thomson from StressMarq Biosciences Inc.

About StressMarq Biosciences

Established in 2007, StressMarq Biosciences Inc. is a supplier of life science products that operates out of Victoria, Canada with a small, but dedicated group of scientists. Headed by our CEO and President Dr. Ariel Louwrier, StressMarq provides the research community with high-quality reagents backed with rigorous quality control data, expert scientific support, and fast international delivery.

“Discovery through partnership, Excellence through quality”

With over 7,000 products, our growth can be attributed to the continual production of cutting edge research products. Our diverse portfolio of primary antibodies, antibody conjugates, proteins, immunoassay kits and small molecules bridges across the life sciences, including products for cancer research, cardiovascular disease, cell signaling and neuroscience. To aid research worldwide, StressMarq has an extensive network of international distributors that allow us to supply reagents to over 50 countries.

In the years to come, StressMarq will continue to aid life science research by providing “Discovery through partnership, and Excellence through quality”.


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Last updated: Jan 27, 2020 at 2:38 AM

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