title: Mahogunin ring finger 1 confers cytoprotection against mutant SOD1 aggresomes and is defective in an ALS mouse model.
abstract: Proteotoxicity of misfolded, disease-causing proteins is deeply implicated in the pathomechanisms for neurodegenerative diseases including copper-zinc superoxide dismutase (SOD1)-linked amyotrophic lateral sclerosis (ALS). However, the precise cellular quality control (QC) mechanisms against aggregation of misfolded mutant SOD1 proteins remain elusive. Here, we found that the Mahogunin ring finger-1 (MGRN1) E3 ubiquitin ligase, which catalyzes mono-ubiquitination to the substrate, was dysregulated in the cellular and mouse models of ALS and that it preferentially interacted with various mutant forms of SOD1. Intriguingly, the motor neurons of presymptomatic ALS mice have diminished MGRN1 cytoplasmic distribution. MGRN1 was partially recruited to mutant SOD1 inclusions where they were positive for p62 and Lamp2. Moreover, overexpression of MGRN1 reduced mutant SOD1 aggregation and alleviated its proteotoxic effects on cells. Taken together, our findings suggest that MGRN1 contributes to the clearance of toxic mutant SOD1 inclusions likely through autophagic pathway, and, most likely, the sequestration of MGRN1 sensitizes motor neurons to degeneration in the ALS mouse model. Furthermore, the present study identifies the MGRN1-mediated protein QC mechanism as a novel therapeutic target in neurodegenerative diseases.
authors.affiliation: Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan 342011, India.
authors.forename: Deepak
authors.initials: D
authors.lastname: Chhangani
authors.affiliation: Department of Neuroscience and Pathobiology Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Fumito
authors.initials: F
authors.lastname: Endo
authors.affiliation: Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan 342011, India.
authors.forename: Ayeman
authors.initials: A
authors.lastname: Amanullah
authors.affiliation: Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan 342011, India.
authors.forename: Arun
authors.initials: A
authors.lastname: Upadhyay
authors.affiliation: Department of Neuroscience and Pathobiology Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan 342011, India.
authors.forename: Ribhav
authors.initials: R
authors.lastname: Mishra
authors.affiliation: Department of Neuroscience and Pathobiology Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. Electronic address: kojiyama@riem.nagoya-u.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanaka
authors.affiliation: Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Rajasthan 342011, India. Electronic address: amit@iitj.ac.in.
authors.forename: Amit
authors.initials: A
authors.lastname: Mishra
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000473:pathology*; D000818:Animals; D019556:COS Cells; D002470:Cell Survival; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C470689:Mgrn1 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Amyotrophic lateral sclerosis; Cytotoxicity; MGRN1; Protein aggregation; SOD1