title: PTEN deletion enhances survival, neurite outgrowth and function of dopamine neuron grafts to MitoPark mice.
abstract: Clinical trials in Parkinson's disease have shown that transplants of embryonic mesencephalic dopamine neurons form new functional connections within the host striatum, but the therapeutic benefits have been highly variable. One obstacle has been poor survival and integration of grafted dopamine neurons. Activation of Akt, a serine/threonine kinase that promotes cell survival and growth, increases the ability of neurons to survive after injury and to regenerate lost neuronal connections. Because the lipid phosphatase, phosphatase and tensin homolog (PTEN) inhibits Akt, we generated a mouse with conditional knock-out of PTEN in dopamine neurons, leading to constitutive expression of Akt in these neurons. Ventral mesencephalic tissue from dopamine phosphatase and tensin homologue knock-out or control animals was then transplanted bilaterally into the dopamine depleted striata of MitoPark mice that express a parkinsonian phenotype because of severe respiratory chain dysfunction in dopamine neurons. After transplantation into MitoPark mice, PTEN-deficient dopamine neurons were less susceptible to cell death, and exhibited a more extensive pattern of fibre outgrowth compared to control grafts. Voltammetric measurements demonstrated that dopamine release and reuptake were significantly increased in the striata of animals receiving dopamine PTEN knock-out transplants. These animals also displayed enhanced spontaneous and drug-induced locomotor activity, relative to control transplanted MitoPark mice. Our results suggest that disinhibition of the Akt-signalling pathway may provide a valuable strategy to enhance survival, function and integration of grafted dopamine neurons within the host striatum and, more generally, to improve survival and integration of different forms of neural grafts.
authors.affiliation: Integrative Neuroscience Branch, National Institute on Drug Abuse Intramural Research Programme, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: YaJun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Granholm
authors.forename: Kyounghee
authors.initials: K
authors.lastname: Huh
authors.forename: Lufei
authors.initials: L
authors.lastname: Shan
authors.forename: Oscar
authors.initials: O
authors.lastname: Diaz-Ruiz
authors.forename: Nasir
authors.initials: N
authors.lastname: Malik
authors.forename: Lars
authors.initials: L
authors.lastname: Olson
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Hoffer
authors.forename: Carl R
authors.initials: CR
authors.lastname: Lupica
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Hoffman
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Bäckman
mesh_terms: D000818:Animals; D002452:Cell Count; D002470:Cell Survival / Q000235:genetics*; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D006085:Graft Survival / Q000235:genetics*; D008636:Mesencephalon / Q000166:cytology / Q000378:metabolism / Q000637:transplantation*; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics; D016501:Neurites / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000601:surgery*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D014446:Tyrosine 3-Monooxygenase; D051059:PTEN Phosphohydrolase