How Neurodegenerative Diseases are Affected by Gamma Synuclein Aggregation

The synuclein family of proteins is made up of alpha, beta, and gamma synuclein. The SNCG gene encodes Gamma synuclein. This is overexpressed in cancers of the breast, ovary, colon, liver and cervix.^1-4

Lewy bodies can form through aggregation of alpha synuclein. This has also been linked to neurodegenerative disorders such Parkinson’s Disease (PD). Alpha synuclein aggregation is inhibited by beta synuclein. The role of gamma synuclein in neurodegenerative diseases, however, is not fully understood.

Gamma Synuclein in CSF

For certain cancers, gamma synuclein can be used as a biomarker.⁵ In patients with Alzheimer’s Disease (AD) and Creutzfeldt-Jakob Disease (CJD) the concentration of gamma synuclein in cerebrospinal fluid (CSF) is also increased.⁶ Elevated CSF gamma synuclein concentration are also observed in aged patients with AD, Lewy body disease (LBD) and vascular dementia (CVD).⁷

Gamma Synuclein Expression in Mice

The memory capacity of mice improves when the gamma synuclein gene is inactivated in them.⁸ In contrast to this, neurodegenerative pathology develops in transgenic mice expressing high levels of gamma synuclein.⁹ This neurodegeneration is associated with gamma synuclein aggregation into spheroids and linear fibrils.⁹

Gamma Synuclein Oxidation and Aggregation

It is thought that gamma synuclein exists in a natively unfolded conformation, and that it is prone to aggregate into small, soluble oligomers in solution.¹⁰ Gamma synuclein aggregates into larger lesions as a result of oxidation at methionine 38. In human brains containing Lewy bodies, these inclusions are found within neurons and neurites in the amygdala and substantia nigra.¹¹ In some ALS cases, gamma synuclein accumulation is also seen, where it accumulates into inclusions causing motor neuron death.¹²

Interactions with Alpha Synuclein

Similar structures are seen in alpha and gamma synuclein and both display tendencies to aggregate.⁹ Brains with PD and Dementia with Lewy Bodies (DLB) display both alpha and gamma synuclein lesions.¹³ AD patients’ brains also display colocalization of oxidized gamma synuclein and phosphorylated alpha synuclein.¹¹

Furthermore, it is thought that alpha and gamma synuclein interact and promote each other’s aggregation.¹⁴ Gamma synuclein can seed the aggregation of alpha synuclein through the oxidation of gamma synuclein at metathionine 39 and tyrosine 39, two of the most easily oxidized residues.¹⁵

It is thought that gamma synuclein is secreted from neurons via exosomes, transmitted to glial cells, and that these promote aggregation of intracellular proteins.¹⁵ This enables it to spread in a prion-like manner and seed the aggregation of alpha synuclein seen in synucleinopathies.¹⁵

Gamma Synuclein Preformed Fibrils (PFFs)

StressMarq’s active gamma synuclein preformed fibrils (PFFs) seed the aggregation of gamma synuclein monomers, resulting in the protein aggregation seen in neurodegenerative diseases.

TEM of Active Human Recombinant Gamma Synuclein Protein Preformed Fibrils (Type 1) (SPR-459). Image Credit: StressMarq Biosciences

References and Further Reading

1. Bruening, W. et al. Synucleins are expressed in the majority of breast and ovarian carcinomas and in preneoplastic lesions of the ovary. Cancer 88, 2154–2163 (2000).
2. Guo, J. et al. Neuronal protein synuclein gamma predicts poor clinical outcome in breast cancer. J. Cancer 121, 1296–1305 (2007).
3. Hu, H. et al. Tumor cell-microenvironment interaction models coupled with clinical validation reveal CCL2 and SNCG as two predictors of colorectal cancer hepatic metastasis. Cancer Res. 15, 5485–5493 (2009).
4. Liu, H. et al. Loss of epigenetic control of synuclein-gamma gene as a molecular indicator of metastasis in a wide range of human cancers. Cancer Res. 65, 7635–7643 (2005).
5. Surguchov, A. γ-Synuclein as a Cancer Biomarker: Viewpoint and New Approaches. Oncomedicine. 1,1-3 (2016).
6. Oeckl, P. et al. Alpha-, Beta-, and Gamma-synuclein Quantification in Cerebrospinal Fluid by Multiple Reaction Monitoring Reveals Increased Concentrations in Alzheimer′s and Creutzfeldt-Jakob Disease but No Alteration in Synucleinopathies. Mol Cell Proteomics. 2016 Oct; 15(10): 3126–3138.
7. Doherty J, McIntosh G, Milton I. Alpha- and gamma-synuclein proteins are present in cerebrospinal fluid and are increased in aged subjects with neurodegenerative and vascular changes. Dement Geriatr Cogn Disord. 2008;26(1):32-42
8. Kokhan et al. Differential involvement of the gamma-synuclein in cognitive abilities on the model of knockout mice. BMC Neuroscience 2013, 14:53
9. Ninkina N, Peters O, Millership S, Salem H, van der Putten H, Buchman VL. Gamma-synucleinopathy: neurodegeneration associated with overexpression of the mouse protein. Hum Mol Genet 2009, 18(10):1779–1794.
10. Golebiewska, U. et al. Defining the Oligomerization State of γ-Synuclein in Solution and in Cells. Biochem. 2014 53(2): 293–299.
11. Surgucheva et al. New α- and γ-synuclein immunopathological lesions in human brain. Acta Neuropathologica Communications 2014, 2:132
12. Peters OM, Millership S, Shelkovnikova TA, et al. Selective pattern of motor system damage in gamma-synuclein transgenic mice mirrors the respective pathology in amyotrophic lateral sclerosis. Neurobiol Dis 2012;48: 124–131.
13. Galvin, J.E. Axon pathology in Parkinson’s disease and Lewy body dementia hippocampus contains a-, b-, and g-synuclein. Proc Natl Acad Sci USA. 1999 Nov 9; 96(23): 13450–13455.
14. Surguchov A: Synucleins: are they two-edged swords? J Neurosci Res 2013, 91(2):16
15. Surgucheva I, Sharov VS, Surguchov A: γ-Synuclein: seeding of α-synuclein aggregation and transmission between cells. Biochemistry 2012, 51(23):4743–4754.

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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