The synuclein family of proteins consists of alpha, beta, and gamma synuclein.  Gamma synuclein is encoded by the SNCG gene, which is overexpressed in breast, ovary, colon, liver, and cervix cancers.^1-4  While alpha synuclein can aggregate to form Lewy bodies and has been linked to neurodegenerative disorders such Parkinson’s Disease (PD), and beta synuclein is thought to inhibit alpha synuclein aggregation, the role of gamma synuclein in neurodegenerative diseases is not as well understood.

Gamma Synuclein in CSF

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

Gamma Synuclein Expression in Mice

When the gamma synuclein gene is inactivated in mice, their memory capacity improves.⁸  Conversely, transgenic mice expressing high levels of gamma synuclein develop neurodegenerative pathology.⁹ This neurodegeneration is associated with gamma synuclein aggregation into spheroids and linear fibrils.⁹

Gamma Synuclein Oxidation and Aggregation

Gamma synuclein is thought to exist in a natively unfolded conformation, and is prone to aggregate into small, soluble oligomers in solution.¹⁰  Oxidation at methionine 38 causes gamma synuclein to aggregate into larger lesions. These inclusions are found within neurons and neurites in the amygdala and substantia nigra in human brains containing Lewy bodies.¹¹ Gamma synuclein accumulation is also seen in some ALS cases, where it can accumulate into inclusions causing motor neuron death.¹²

Interactions with Alpha Synuclein

Alpha and gamma synuclein have similar structures and tendencies to aggregate.⁹  Both alpha and gamma synuclein lesions can be seen in brains with PD and Dementia with Lewy Bodies (DLB).¹³ Colocalization of oxidized gamma synuclein and phosphorylated alpha synuclein can also be seen in AD patients’ brains.¹¹ Additionally, alpha and gamma synuclein are thought to interact and promote each other’s aggregation.¹⁴  The oxidation of gamma synuclein at metathionine 39 and tyrosine 39, two of the most easily oxidized residues, allows gamma synuclein to seed the aggregation of alpha synuclein.¹⁵ Gamma synuclein is thought to be secreted from neurons via exosomes, transmitted to glial cells, and promote aggregation of intracellular proteins.¹⁵ This allows 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, leading to the protein aggregation seen in neurodegenerative diseases. Learn more

TEM of Active Human Recombinant Gamma Synuclein Protein Preformed Fibrils (Type 1) (SPR-459)

References

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