Synuclein

Synuclein refers to a small family of soluble presynaptic proteins consisting of alpha-synuclein, beta-synuclein, and gamma-synuclein. They are encoded by the SNCA, SNCB, and SNCG genes, respectively, and are highly expressed in the nervous system, particularly in presynaptic terminals of the brain.

Biochemically, synucleins are predominantly intrinsically disordered in their monomeric form. They contain an N-terminal region that binds phospholipid membranes and can adopt an alpha-helical structure upon membrane association, a central non-amyloid component (NAC) domain that influences aggregation, and a negatively charged C-terminal tail. They can exist as monomers or form oligomeric species, with the exact physiological form being a matter of ongoing research and debate. The proteins are thought to participate in synaptic vesicle regulation and neurotransmitter release, possibly by modulating SNARE complex assembly and vesicle cycling, and may also influence lipid homeostasis and synaptic plasticity.

Pathologically, alpha-synuclein is central to several neurodegenerative diseases known as synucleinopathies. Misfolded alpha-synuclein aggregates form Lewy bodies and Lewy neurites in Parkinson’s disease and dementia with Lewy bodies, and glial inclusions containing alpha-synuclein are seen in multiple system atrophy. Genetic alterations, including SNCA gene duplications or triplications and missense mutations (e.g., A53T, A30P, E46K), cause familial forms of Parkinson’s disease and can enhance aggregation and toxicity. Post-translational modifications, such as phosphorylation at Ser129 and truncation, modulate aggregation propensity and pathogenicity.

In research and clinical settings, synuclein serves as a biomarker and therapeutic target. Misfolded or aggregated forms can be detected in cerebrospinal fluid or blood, and various strategies aim to reduce aggregation or impede prion-like propagation.