title: E6-AP association promotes SOD1 aggresomes degradation and suppresses toxicity.
abstract: Protein aggregation and ordered fibrillar amyloid deposition inside and outside of the central nervous system cells is the common pathologic hallmark of most aging-related neurodegenerative disorders. Dominant mutations in the gene encoding superoxide dismutase 1 (SOD1) protein are linked to familial amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive degeneration of motor neurons, leading to muscle paralysis and death. The major histochemical hallmark in the remaining motor neurons of ALS is the intracellular accumulation of ubiquitinated inclusions consisting of insoluble aberrant protein aggregates. However, the molecular pathomechanisms underlying the process have been elusive. Here for the first time, we report that E6-AP, a homologous to E6-AP C terminus-type E3 ubiquitin ligase depleted in ALS mouse models before neurodegeneration. E6-AP coimmunoprecipitates with the SOD1 protein and is predominantly mislocalized in mutant SOD1-containing inclusion bodies. Overexpression of E6-AP increases the ubiquitination and facilitates degradation of SOD1 proteins. Finally, we show that the overexpression of E6-AP suppresses the aggregation and cell death mediated by mutated SOD1 proteins and cellular protective effect is more prominent when E6-AP is overexpressed along with Hsp70. These data suggest that enhancing the activity of E6-AP ubiquitin ligase might be a viable therapeutic strategy to eliminate mutant SOD1-mediated toxicity in ALS.
authors.affiliation: Biology Laboratory, Indian Institute of Technology Rajasthan, Jodhpur, India. amit@iitj.ac.in
authors.forename: Amit
authors.initials: A
authors.lastname: Mishra
authors.forename: Megha
authors.initials: M
authors.lastname: Maheshwari
authors.forename: Deepak
authors.initials: D
authors.lastname: Chhangani
authors.forename: Noriko
authors.initials: N
authors.lastname: Fujimori-Tonou
authors.forename: Fumito
authors.initials: F
authors.lastname: Endo
authors.forename: Ajay Prakash
authors.initials: AP
authors.lastname: Joshi
authors.forename: Nihar Ranjan
authors.initials: NR
authors.lastname: Jana
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanaka
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002449:Cell Aggregation; D002470:Cell Survival; D002478:Cells, Cultured; D002479:Inclusion Bodies / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D013482:Superoxide Dismutase / 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; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases