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Dopaminergic pathway reconstruction by Akt/Rheb‐induced axon regeneration
Author(s) -
Kim Sang Ryong,
Chen Xiqun,
Oo Tinmarla F.,
Kareva Tatyana,
Yarygina Olga,
Wang Chuansong,
During Matthew,
Kholodilov Nikolai,
Burke Robert E.
Publication year - 2011
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22383
Subject(s) - neuroscience , rheb , protein kinase b , substantia nigra , pi3k/akt/mtor pathway , biology , dopaminergic , axon , tsc1 , signal transduction , microbiology and biotechnology , dopamine , mtorc1
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. Interpretation: 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. ANN NEUROL 2011