title: Phosphatase and tensin homologue/protein kinase B pathway linked to motor neuron survival in human superoxide dismutase 1-related amyotrophic lateral sclerosis.
abstract: Gene expression profiling has been used previously with spinal cord homogenates and laser capture microdissected motor neurons to determine the mechanisms involved in neurodegeneration in amyotrophic lateral sclerosis. However, while cellular and animal model work has focused on superoxide dismutase 1-related amyotrophic lateral sclerosis, the transcriptional profile of human mutant superoxide dismutase 1 motor neurons has remained undiscovered. The aim of this study was to apply gene expression profiling to laser captured motor neurons from human superoxide dismutase 1-related amyotrophic lateral sclerosis and neurologically normal control cases, in order to determine those pathways dysregulated in human superoxide dismutase 1-related neurodegeneration and to establish potential pathways suitable for therapeutic intervention. Identified targets were then validated in cultured cell models using lentiviral vectors to manipulate the expression of key genes. Microarray analysis identified 1170 differentially expressed genes in spinal cord motor neurons from superoxide dismutase 1-related amyotrophic lateral sclerosis, compared with controls. These genes encoded for proteins in multiple functional categories, including those involved in cell survival and cell death. Further analysis determined that multiple genes involved in the phosphatidylinositol-3 kinase signalling cascade were differentially expressed in motor neurons that survived the disease process. Functional experiments in cultured cells and primary motor neurons demonstrate that manipulating this pathway by reducing the expression of a single upstream target, the negative phosphatidylinositol-3 kinase regulator phosphatase and tensin homology, promotes a marked pro-survival effect. Therefore, these data indicate that proteins in the phosphatidylinositol-3 kinase pathway could represent a target for therapeutic manipulation in motor neuron degeneration.
authors.affiliation: Academic Neurology Unit, Shefﬁeld Institute for Translational Neuroscience, University of Shefﬁeld, Shefﬁeld, UK. j.kirby@sheffield.ac.uk
authors.forename: Janine
authors.initials: J
authors.lastname: Kirby
authors.forename: Ke
authors.initials: K
authors.lastname: Ning
authors.forename: Laura
authors.initials: L
authors.lastname: Ferraiuolo
authors.forename: Paul R
authors.initials: PR
authors.lastname: Heath
authors.forename: Azza
authors.initials: A
authors.lastname: Ismail
authors.forename: Su-Wei
authors.initials: SW
authors.lastname: Kuo
authors.forename: Chiara F
authors.initials: CF
authors.lastname: Valori
authors.forename: Laura
authors.initials: L
authors.lastname: Cox
authors.forename: Basil
authors.initials: B
authors.lastname: Sharrack
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Wharton
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ince
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.forename: Mimoun
authors.initials: M
authors.lastname: Azzouz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D018929:Cell Culture Techniques; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000235:genetics / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000201:enzymology*; D009154:Mutation; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis*; D058539:Phosphatidylinositol 3-Kinase / Q000096:biosynthesis*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013482:Superoxide Dismutase / Q000235:genetics / Q000502:physiology*; D000072105:Superoxide Dismutase-1
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D058539:Phosphatidylinositol 3-Kinase; D051059:PTEN Phosphohydrolase