金属神经化学5(英文版).pptVIP

Dismutation of two molecules of superoxide anion (O2?) by the Cu, Zn-SOD. The scheme shows successive breaking and formation of the inter-metallic bridge formed by His61, upon changes in copper oxidation state (CuII–CuI). Motorneurondisease amyotrophiclateral sclerosis (ALS) There is now little doubt that the prime cause of the motorneuron disease amyotrophic lateral sclerosis (ALS) is related to misfolding and aggregation of the metalloenzyme Cu/Zn superoxide dismutase (SOD1). Hypothetical outline of the folding and aggregation pathways of SOD1 and how these can be linked to neurotoxicity in ALS. CCS, copper chaperone for SOD1. The EM image of the SOD1 fibrils is adapted from the article of Chattopadhyay et al. (5) in this issue of PNAS, and the fibrillar propensities of the SOD1 sequence as predicted by WALZ are shown in blue. It remains now to find out whether SOD1 fibrillation is linked to neurotoxicity and deposition of proteinaceous inclusions, along the same lines as have been implicated for other neurodegenerative diseases. Stathopulos PB, et al. (2003) Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis show enhanced formation of aggregates in vitro. Proc Natl Acad Sci USA 100:7021–7026. 2. DiDonato M, et al. (2003) ALS mutants of human superoxide dismutase form fibrous aggregates via framework destabilization. J Mol Biol 332:601–615. 3. Chattopadhyay M, et al. (2008) Initiation and elongation in fibrillation of ALS-linked superoxide dismutase. Proc Natl Acad Sci USA 105:18663–18668. 4. Chiti F, Dobson CM (2006) Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem 75:333–366. 5. David R. Brown, Brain proteins that mind metals: a neurodegenerative perspective, Dalton Trans., 2009, 4069–4076. * SOD (Superoxide Dismutase) Cu, Zn, Mn, Fe, Ni Cu–Zn Superoxide Dismutase 与 Familial Amyotrophic Lateral Sclerosis (ALS), also known as motor neuron disease or Lou Gehrig’s disease Failure