SIAH1, E3 Ubiquitin Ligase

Seven in absentia homolog 1 (SIAH-1) is a member of the RING-finger-containing E3 ubiquitin ligases. Alpha-synuclein and synphilin-1 are substrates of SIAH-1 , both proteins are involved in the development of Parkinson's disease (PD). Mutations in Parkin, another E3 ubiquitin ligase which ubiquinates synphilin-1 and glycosylated alpha-synuclein, have been defined as a major cause of autosomal recessive PD. The role of SIAH-1 in PD is highlighted by the fact that SIAH-1 is a component of the Lewy bodies and plays a role in apoptosis caused by nitric oxide (NO) induced oxidative stress. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) a classic glycolytic enzyme, and multi-functional protein. GAPDH plays role as a mediator for cell death. GAPDH translocates to the nucleus under a variety of stressors/conditions, most of which are associated with oxidative stress. Sequential steps lead to nuclear translocation of GAPDH during cell death; 1] a catalytic cysteine in GAPDH (C150 in rat GAPDH) is S-nitrosylated by nitric oxide (NO) which is generated from inducible nitric oxide synthase (iNOS) and/or neuronal NOS (nNOS); 2] the modified GAPDH becomes capable of binding with Siah1, an E3 ubiquitin ligase, and stabilizes it;3] the GAPDH-Siah protein complex translocates to the nucleus, dependent on Siah1's nuclear localization signal, and degrades Siah1's substrates in the nucleus, which results in cytotoxicity. GAPDH may be genetically associated with late-onset Alzheimer's disease. (-)-deprenyl, which has been used as a monoamine oxidase inhibitor for Parkinson's disease, binds to GAPDH and has neuroprotective actions. The molecular action of this protection is as yet not clear.