AAV transduction of dopamine neurons with constitutively active Rheb protects from neurodegeneration and mediates axon regrowth.
There are currently no therapies that provide either protection or restoration of neuronal function for adult-onset neurodegenerative diseases such as Parkinson's disease (PD). Many clinical efforts to provide such benefits by infusion of neurotrophic factors have failed, in spite of robust effects in preclinical assessments. One important reason for these failures is the difficulty, due to diffusion limits, of providing these protein molecules in sufficient amounts to the intended cellular targets in the central nervous system. This challenge suggests an alternative approach, that of viral vector transduction to directly activate the intracellular signaling pathways that mediate neurotrophic effects. To this end we have investigated the ability of a constitutively active form of the GTPase Rheb, an important activator of mammalian target of rapamycin (mTor) signaling, to mediate neurotrophic effects in dopamine neurons of the substantia nigra (SN), a population of neurons affected in PD. We find that constitutively active hRheb(S16H) induces many neurotrophic effects in mice, including abilities to both preserve and restore the nigrostriatal dopaminergic axonal projections in a highly destructive neurotoxin model. We conclude that direct viral vector transduction of vulnerable neuronal populations to activate intracellular neurotrophic signaling pathways offers promise for the treatment of neurodegenerative disease.
Department of Neurology, Columbia University, New York, New York 10032, USA.
Sang Ryong
SR
Kim
Tatyana
T
Kareva
Olga
O
Yarygina
Nikolai
N
Kholodilov
Robert E
RE
Burke
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism*; D039642:Eukaryotic Initiation Factors; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism; D016627:Oxidopamine / Q000009:adverse effects; D010300:Parkinson Disease / Q000517:prevention & control* / Q000628:therapy; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D014161:Transduction, Genetic
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D009479:Neuropeptides; D010750:Phosphoproteins; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; D016627:Oxidopamine; D020559:Monomeric GTP-Binding Proteins