title: Curcumin binds to the pre-fibrillar aggregates of Cu/Zn superoxide dismutase (SOD1) and alters its amyloidogenic pathway resulting in reduced cytotoxicity.
abstract: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons. Unfortunately, effective therapeutics against this disease is still not available. Almost 20% of familial ALS (fALS) is suggested to be associated with pathological deposition of superoxide dismutase (SOD1). Evidences suggest that SOD1-containing pathological inclusions in ALS exhibit amyloid like properties. An effective strategy to combat ALS may be to inhibit amyloid formation of SOD1 using small molecules. In the present study, we observed the fibrillation of one of the premature forms of SOD1 (SOD1 with reduced disulfide) in the presence of curcumin. Using ThT binding assay, AFM, TEM images and FTIR, we demonstrate that curcumin inhibits the DTT-induced fibrillation of SOD1 and favors the formation of smaller and disordered aggregates of SOD1. The enhancement in curcumin fluorescence on the addition of oligomers and pre-fibrillar aggregates of SOD1 suggests binding of these species to curcumin. Docking studies indicate that putative binding site of curcumin may be the amyloidogenic regions of SOD1. Further, there is a significant increase in SOD1 mediated toxicity in the regime of pre-fibrillar and fibrillar aggregates which is not evident in curcumin containing samples. All these data suggest that curcumin reduces toxicity by binding to the amyloidogenic regions of the species on the aggregation pathway and blocking the formation of the toxic species. Nanoparticles of curcumin with higher aqueous solubility show similar aggregation control as that of curcumin bulk. This suggests a potential role for curcumin in the treatment of ALS.
authors: Department of Chemistry, Indian Institute of Technology, Delhi, Hauz Khas, New Delhi, India.
authors: Nidhi K
authors: NK
authors: Bhatia
authors: Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi, Hauz Khas, New Delhi, India.
authors: Ankit
authors: A
authors: Srivastava
authors: Department of Chemistry, Indian Institute of Technology, Delhi, Hauz Khas, New Delhi, India.
authors: Nidhi
authors: N
authors: Katyal
authors: Department of Chemistry, Indian Institute of Technology, Delhi, Hauz Khas, New Delhi, India.
authors: Nidhi
authors: N
authors: Jain
authors: Department of Chemistry, Indian Institute of Technology, Delhi, Hauz Khas, New Delhi, India.
authors: M Ashhar I
authors: MA
authors: Khan
authors: Kusuma School of Biological Sciences, Indian Institute of Technology, Delhi, Hauz Khas, New Delhi, India.
authors: Bishwajit
authors: B
authors: Kundu
authors: Department of Chemistry, Indian Institute of Technology, Delhi, Hauz Khas, New Delhi, India. Electronic address: sdeep@chemistry.iitd.ac.in.
authors: Shashank
authors: S
authors: Deep
mesh_terms: D000682:Amyloid / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism / Q000633:toxicity*; D002478:Cells, Cultured; D003474:Curcumin / Q000737:chemistry / Q000493:pharmacokinetics*; D019610:Cytoprotection / Q000187:drug effects; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D066329:Protein Aggregates / Q000187:drug effects*; D011485:Protein Binding; D055503:Protein Multimerization / Q000187:drug effects; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D000682:Amyloid; D066329:Protein Aggregates; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D003474:Curcumin
keywords: Amyloid; Amyotrophic Lateral Sclerosis; Curcumin; Inhibitor; Microscopy; Superoxide dismutase