SNCAIP

The SNCAIP gene encodes synphilin-1, a multi-domain protein with a complex structure integral to neuronal function and implicated in neurodegenerative diseases. Structurally, synphilin-1 is composed of approximately 919 amino acids and is characterized by several functional domains, notably including six ankyrin repeats and a central coiled-coil domain spanning residues 510–557. These domains are typical protein-protein interaction motifs, facilitating synphilin-1's ability to interact with partner proteins such as alpha-synuclein (SNCA). SNCAIP binds to the N-terminal region of SNCA, allowing synphilin-1 to play a role in the formation of cytosolic inclusions mimicking Lewy bodies, which are hallmark features of synucleinopathies. The ankyrin repeats provide scaffolding for additional protein interactions, while the coiled-coil domain is crucial for the association with alpha-synuclein and possibly other synaptic or vesicular components.^[8][9]

SNCAIP encodes synphilin-1, a cytoplasmic protein that interacts with alpha-synuclein in neuronal tissue and is involved in a variety of physiological processes related to synaptic function and protein homeostasis. Synphilin-1 is developmentally localized to synaptic terminals and participates in the regulation of synaptic vesicle trafficking. It may act as a scaffold protein, contributing to cellular processes like protein degradation through the ubiquitin-proteasome system and autophagy. Experimental evidence suggests that binding of synphilin-1 to alpha-synuclein can modulate synaptic vesicle dynamics, potentially impacting neurotransmitter release and synaptic plasticity. Synphilin-1’s cytoprotective effects include inhibiting mitochondrial dysfunction, reducing reactive oxygen species production, and promoting neuronal survival under certain conditions.^{[10][11][12][13]}

Synphilin-1 undergoes ubiquitination. Parkin (an E3 ligase) modifies synphilin-1 and, together with α-synuclein, promotes the formation of ubiquitin-positive inclusion bodies.^[14] Mutations in parkin gene disrupt this activity. Additional E3 ligases, including SIAH1 and SIAH2, also ubiquitinate synphilin-1, influencing whether the protein is directed to proteasomal degradation or accumulates in inclusions.^[15] Inclusions containing α-synuclein and synphilin-1 share features with aggresomes, which may act to sequester misfolded proteins and limit cellular toxicity.^[16]

Clinically, synphilin-1 is heavily implicated in neurodegenerative diseases, particularly Parkinson’s disease (PD). It serves as a major component of Lewy bodies—the pathological protein aggregates characteristic of PD—and contributes to the formation of these cytoplasmic inclusions. While wild-type synphilin-1 may help sequester potentially toxic protein aggregates, certain isoforms and mutants, such as synphilin-1A, are highly aggregation-prone and associated with neuronal toxicity and degeneration. Genetic variation and altered methylation of the SNCAIP gene are linked with increased vulnerability to PD and related synucleinopathies. Thus, synphilin-1 exerts complex effects on neuronal health, acting as both a potential protector and a contributor to disease pathology depending on its expression, isoform, and interaction context.^{[17][18][13][19]}

Beyond Parkinson’s disease, synphilin-1 has recently been implicated in glioblastoma. Transcriptomic and single-cell RNA sequencing analyses identified SNCAIP among histone lactylation related genes upregulated in glioblastoma, with elevated expression correlating with poorer patient survival.^[20] This has raised interest in synphilin-1 as a potential biomarker in cancer biology.

SNCAIP has been shown to interact with:

• Alpha-synuclein^{[5][21][22][23]} and
• Parkin (ligase).^[24]