Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson's disease

doi:10.1073/pnas.0606401103

Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson's disease

Departments of *Neurology and
^§Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032; and
^†Neurologix Research and
^‡Human Cancer Genetics Program, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved October 11, 2006 (received for review July 27, 2006)

Abstract

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.

Footnotes

^¶To whom correspondence should be addressed at:
Department of Neurology, Room 306, Black Building, Columbia University Medical Center, 650 West 168th Street, New York, NY 10032.
E-mail: rb43{at}columbia.edu
Author contributions: V.R., C.H., M.J.D., N.K., and R.E.B. designed research; V.R., C.H., T.K., M.R., R.B., and N.K. performed research; V.R., C.H., and R.E.B. analyzed data; and V.R., C.H., R.B., M.J.D., N.K., and R.E.B. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
Abbreviations:

AAV,

adeno-associated virus;

PD,

Parkinson's disease;

DA,

dopamine;

SN,

substantia nigra;

Myr,

myristoylated;

SNpc,

SN pars compacta;

TH,

tyrosine hydroxylase;

HVA,

homovanillic acid;

6OHDA,

6-hydroxydopamine.
Freely available online through the PNAS open access option.