Seven in absentia homolog 1 (SIAH1) and 2 (SIAH2) are E3 ubiquitin-protein ligases that mediates ubiquitination of a number of target proteins including Synphilin-1 (SNCAIP) (Nagano et al. 2003) and alpha-synuclein (SNCA) (Liani et al. 2004, Lee et al. 2008). Ubiquitination of SNCA by SIAH1 is disrupted by the Parkinson's Disease (PD)-linked A30P mutation but not by the A53T mutation. SIAH1 binds the E2 ubiquitin-conjugating enzyme UBE2L6 (UBCH8) (Lee et al. 2008). This facilitates the mono- and di-ubiquitination of SNCA in vivo, but does not target SNCA for proteasomal degradation, rather it promotes SNCA aggregation and enhances toxicity (Lee et al. 2008). Monoubiquitinated SNCA may work as a seed for aggregation (Engelender 2008) and recruit other PD-related proteins, such as SNCAIP and UCHL1.