Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson's disease.
Despite promising preclinical studies, neurotrophic factors have not yet achieved an established role in the treatment of human neurodegenerative diseases. One impediment has been the difficulty in providing these macromolecules in sufficient quantity and duration at affected sites. An alternative approach is to directly activate, by viral vector transduction, intracellular signaling pathways that mediate neurotrophic effects. We have evaluated this approach in dopamine neurons of the substantia nigra, neurons affected in Parkinson's disease, by adeno-associated virus 1 transduction with a gene encoding a myristoylated, constitutively active form of the oncoprotein Akt/PKB. Adeno-associated virus Myr-Akt has pronounced trophic effects on dopamine neurons of adult and aged mice, including increases in neuron size, phenotypic markers, and sprouting. Transduction confers almost complete protection against apoptotic cell death in a highly destructive neurotoxin model. Activation of intracellular neurotrophic signaling pathways by vector transfer is a feasible approach to neuroprotection and restorative treatment of neurodegenerative disease.
Ries
Vincent
V
Department of Neurology, Columbia University College of Physicians and Surgeons, 650 West 168th Street, New York, NY 10032, USA.
Henchcliffe
Claire
C
Kareva
Tatyana
T
Rzhetskaya
Margarita
M
Bland
Ross
R
During
Matthew J
MJ
Kholodilov
Nikolai
N
Burke
Robert E
RE
D000818:Animals; D004195:Disease Models, Animal; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000473:pathology / Q000821:virology; D010300:Parkinson Disease / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051381:Rats; D013378:Substantia Nigra / Q000166:cytology* / Q000201:enzymology / Q000502:physiology*
D007527:Isoenzymes; D009414:Nerve Growth Factors; D051057:Proto-Oncogene Proteins c-akt