title: Degradation of survival motor neuron (SMN) protein is mediated via the ubiquitin/proteasome pathway.
abstract: Homozygous deletion or mutation in the survival motor neuron (SMN)1 gene causes proximal spinal muscular atrophy (SMA), whereas SMN2 acts as a modifying gene that can influence the severity of SMA. It has been suggested that restoration of the SMN protein level in neuronal cells may prevent cell loss and may be helpful for treatment of SMA. Recent studies indicate that the ubiquitin/proteasome pathway is a major system for proteolysis of intracellular proteins. In this study, we investigate whether SMN protein is degraded via the ubiquitin/proteasome pathway. Primary fibroblasts were established from the skin biopsies of SMA patients and the effect of a proteasome inhibitor MG132 and lysosome inhibitor NH(4)Cl on SMN protein level was examined. We found that MG132, but not NH(4)Cl, significantly increased the amount and nuclear accumulation of SMN protein in SMA patient's fibroblasts. Immunoprecipitation/western blot analysis indicated that SMN protein was ubiquitinated in cells. In vitro protein ubiquitination assay also demonstrated that SMN protein could be conjugated with ubiquitin. Taken together, we have provided clear evidences that degradation of SMN protein is mediated via the ubiquitin/proteasome pathway and suggest that proteasome inhibitors may up-regulate SMN protein level and may be useful for the treatment of SMA.
authors.affiliation: Department of Physiology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors.forename: Hui-Chiu
authors.initials: HC
authors.lastname: Chang
authors.forename: Wen-Chun
authors.initials: WC
authors.lastname: Hung
authors.forename: Yen-Ju
authors.initials: YJ
authors.lastname: Chuang
authors.forename: Yuh-Jyh
authors.initials: YJ
authors.lastname: Jong
mesh_terms: D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein; D003546:Cysteine Endopeptidases / Q000502:physiology*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000502:physiology*; D009134:Muscular Atrophy, Spinal / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; D055540:Survival of Motor Neuron 2 Protein; D025801:Ubiquitin / Q000502:physiology*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D007976:Leupeptins; D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein; D025801:Ubiquitin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde