Seven in absentia homolog 1 (SIAH1) and 2 (SIAH2) are E3 ubiquitin-protein ligases that mediate ubiquitination of a number of target proteins including Synphilin-1 (SNCAIP) (Nagano et al. 2003) and alpha-synuclein (Liani et al. 2004). They are inhibited by the 1A isoform of SNCAIP (Szargel et al. 2009). When ubiquitinated by SIAH1, SNCAIP is targetted for proteasomal degradation (Nagano et al. 2003).
Synphilin-1 (SNCAIP) is a presynaptic protein that associates with synaptic vesicles (Ribeiro et al. 2002). It is present in many types of cytoplasmic inclusions, where it colocalizes with alpha-synuclein. It is associated with Parkinson's Disease (PD) because it is an intrinsic component of Lewy bodies (Wakabayashi et al. 2000) and a mutation of the SNCAIP gene has been identified in some PD patients (Marx et al. 2003), suggesting that accumulation of synphilin-1 and its interaction with alpha-synuclein may be relevant for Lewy body formation in PD.
Synphilin-1 (SNCAIP) is ubiquitinated by several other E3 ubiquitin-ligases, including Parkin (Chung et al. 2001) and Dorfin (Ito et al. 2003).