title: Survival of motor neuron protein over-expression prevents calpain-mediated cleavage and activation of procaspase-3 in differentiated human SH-SY5Y cells.
abstract: Spinal muscular atrophy (SMA), a neurodegenerative disorder primarily affecting motor neurons, is the most common genetic cause of infant death. This incurable disease is caused by the absence of a functional SMN1 gene and a reduction in full length survival of motor neuron (SMN) protein. In this study, a neuroprotective function of SMN was investigated in differentiated human SH-SY5Y cells using an adenoviral vector to over-express SMN protein. The pro-survival capacity of SMN was assessed in an Akt/PI3-kinase inhibition (LY294002) model, as well as an oxidative stress (hydrogen peroxide) and excitotoxic (glutamate) model. SMN over-expression in SH-SY5Y cells protected against Akt/phosphatidylinositol 3-kinase (PI3-kinase) inhibition, but not oxidative stress, nor against excitotoxicity in rat cortical neurons. Western analysis of cell homogenates from SH-SY5Y cultures over-expressing SMN harvested pre- and post-Akt/PI3-kinase inhibition indicated that SMN protein inhibited caspase-3 activation via blockade of calpain-mediated procaspase-3 cleavage. This study has revealed a novel anti-apoptotic function for the SMN protein in differentiated SH-SY5Y cells. Finally, the cell death model described herein will allow the assessment of future therapeutic agents or strategies aimed at increasing SMN protein levels.
authors.affiliation: Centre for Neuromuscular and Neurological Disorders, University of Western Australia, WA, Australia. randerton@meddent.uwa.edu.au
authors.forename: R S
authors.initials: RS
authors.lastname: Anderton
authors.forename: B P
authors.initials: BP
authors.lastname: Meloni
authors.forename: F L
authors.initials: FL
authors.lastname: Mastaglia
authors.forename: W K
authors.initials: WK
authors.lastname: Greene
authors.forename: S
authors.initials: S
authors.lastname: Boulos
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002154:Calpain / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D055533:Survival of Motor Neuron 1 Protein / Q000096:biosynthesis* / Q000235:genetics*
chemical_list: C526471:SMN1 protein, human; D055533:Survival of Motor Neuron 1 Protein; D002154:Calpain; D053148:Caspase 3