title: Dopaminergic pathway reconstruction by Akt/Rheb-induced axon regeneration.
abstract: OBJECTIVE
  A prevailing concept in neuroscience has been that the adult mammalian central nervous system is incapable of restorative axon regeneration. Recent evidence, however, has suggested that reactivation of intrinsic cellular programs regulated by protein kinase B (Akt)/mammalian target of rapamycin (mTor) signaling may restore this ability.
  
  
  METHODS
  To assess this possibility in the brain, we have examined the ability of adenoassociated virus (AAV)-mediated transduction of dopaminergic neurons of the substantia nigra (SN) with constitutively active forms of the kinase Akt and the GTPase Ras homolog enriched in brain (Rheb) to induce regrowth of axons after they have been destroyed by neurotoxin lesion.
  
  
  RESULTS
  Both constitutively active myristoylated Akt and hRheb(S16H) induce regrowth of axons from dopaminergic neurons to their target, the striatum. Histological analysis demonstrates that these new axons achieve morphologically accurate reinnervation. In addition, functional reintegration into target circuitry is achieved, as indicated by partial behavioral recovery.
  
  
  CONCLUSIONS
  We conclude that regrowth of axons within the adult nigrostriatal projection, a system that is prominently affected in Parkinson's disease, can be achieved by activation of Akt/mTor signaling in surviving endogenous mesencephalic dopaminergic neurons by viral vector transduction.
authors: Department of Neurology, Columbia University, New York, NY 10032, USA.
authors: Sang Ryong
authors: SR
authors: Kim
authors: Xiqun
authors: X
authors: Chen
authors: Tinmarla F
authors: TF
authors: Oo
authors: Tatyana
authors: T
authors: Kareva
authors: Olga
authors: O
authors: Yarygina
authors: Chuansong
authors: C
authors: Wang
authors: Matthew
authors: M
authors: During
authors: Nikolai
authors: N
authors: Kholodilov
authors: Robert E
authors: RE
authors: Burke
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D000229:Dependovirus / Q000235:genetics; D004298:Dopamine / Q000502:physiology*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020559:Monomeric GTP-Binding Proteins / Q000008:administration & dosage* / Q000235:genetics; D009416:Nerve Regeneration / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000473:pathology / Q000821:virology; D009479:Neuropeptides / Q000008:administration & dosage* / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000008:administration & dosage* / Q000235:genetics; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction / Q000235:genetics; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology / Q000821:virology
chemical_list: D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D020559:Monomeric GTP-Binding Proteins; D004298:Dopamine