Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subthalamic GAD Gene Therapy in a Parkinson's Disease Rat Model
Jia Luo,12Michael G. Kaplitt,3Helen L. Fitzsimons,1*David S. Zuzga,2Yuhong Liu,2Michael L. Oshinsky,2Matthew J. During12
The motor abnormalities of Parkinson's disease (PD) are caused by
alterations in basal ganglia network activity, includingdisinhibition
of the subthalamic nucleus (STN), and excessiveactivity of the major
output nuclei. Using adeno-associated viralvector-mediated somatic
cell gene transfer, we expressed glutamicacid decarboxylase (GAD), the
enzyme that catalyzes synthesisof the neurotransmitter GABA, in
excitatory glutamatergic neuronsof the STN in rats. The transduced
neurons, when driven by electricalstimulation, produced mixed
inhibitory responses associated withGABA release. This phenotypic
shift resulted in strong neuroprotectionof nigral dopamine neurons and
rescue of the parkinsonian behavioralphenotype. This strategy suggests
that there is plasticity betweenexcitatory and inhibitory
neurotransmission in the mammalian brainthat could be exploited for
therapeutic benefit.
1 Functional Genomics and Translational
Neuroscience Laboratory, Department of Molecular Medicine and
Pathology, University of Auckland, Auckland, New Zealand.
2 CNS Gene Therapy Center, Jefferson Medical
College, Philadelphia, PA 19107, USA.
3 Center for
Stereotactic and Functional Neurosurgery, Department of Neurological
Surgery, Weill Medical College of Cornell University, New York, NY
10021, USA.
*
Present address: Neurologix Inc., Delaware Biotechnology
Institute, 15 Innovation Way, Newark, DE 19711, USA.
To whom correspondence should be addressed. E-mail:
m.during{at}auckland.ac.nz
The editors suggest the following Related Resources on Science sites:
P. G. Coune, B. L. Schneider, and P. Aebischer (2012)
Cold Spring Harb Perspect Med
2, a009431
|Abstract »|Full Text »|PDF »
A novel neuroprotective therapy for Parkinson's disease using a viral noncoding RNA that protects mitochondrial Complex I activity.
W.-L. Kuan, E. Poole, M. Fletcher, S. Karniely, P. Tyers, M. Wills, R. A. Barker, and J. H. Sinclair (2012)
J. Exp. Med.
209, 1-10
|Abstract »|Full Text »|PDF »
Delivery of single-chain antibodies (scFvs) directed against the 37/67 kDa laminin receptor into mice via recombinant adeno-associated viral vectors for prion disease gene therapy.
C. Zuber, G. Mitteregger, N. Schuhmann, C. Rey, S. Knackmuss, W. Rupprecht, U. Reusch, C. Pace, M. Little, H. A. Kretzschmar, et al. (2008)
J. Gen. Virol.
89, 2055-2061
|Abstract »|Full Text »|PDF »
A multitarget basal ganglia dopaminergic and GABAergic transplantation strategy enhances behavioural recovery in parkinsonian rats.
K. Mukhida, M. Hong, G.B. Miles, T. Phillips, B.A. Baghbaderani, M. McLeod, N. Kobayashi, A. Sen, L.A. Behie, R.M. Brownstone, et al. (2008)
Brain
131, 2106-2126
|Abstract »|Full Text »|PDF »
Modulation of metabolic brain networks after subthalamic gene therapy for Parkinson's disease.
A. Feigin, M. G. Kaplitt, C. Tang, T. Lin, P. Mattis, V. Dhawan, M. J. During, and D. Eidelberg (2007)
PNAS
104, 19559-19564
|Abstract »|Full Text »|PDF »
Understanding decision-making deficits in neurological conditions: insights from models of natural action selection.
M. J. Frank, A. Scheres, and S. J. Sherman (2007)
Phil Trans R Soc B
362, 1641-1654
|Abstract »|Full Text »|PDF »
Existence of transient functional double-stranded DNA intermediates during recombinant AAV transduction.
J. Wang, J. Xie, H. Lu, L. Chen, B. Hauck, R. J. Samulski, and W. Xiao (2007)
PNAS
104, 13104-13109
|Abstract »|Full Text »|PDF »
STN stimulation and neuroprotection in Parkinson's disease--when beautiful theories meet ugly facts.
P C Warnke (2005)
J. Neurol. Neurosurg. Psychiatry
76, 1186-1187
|Full Text »|PDF »
Dendritic degeneration in neostriatal medium spiny neurons in Parkinson disease.
S. Zaja-Milatovic, D. Milatovic, A. M. Schantz, J. Zhang, K. S. Montine, A. Samii, A. Y. Deutch, and T. J. Montine (2005)
Neurology
64, 545-547
|Abstract »|Full Text »|PDF »
Restoration of receptor-type protein tyrosine phosphatase {eta} function inhibits human pancreatic carcinoma cell growth in vitro and in vivo.
F. Trapasso, S. Yendamuri, K. R. Dumon, R. Iuliano, R. Cesari, B. Feig, R. Seto, L. Infante, H. Ishii, A. Vecchione, et al. (2004)
Carcinogenesis
25, 2107-2114
|Abstract »|Full Text »|PDF »
Circulating Anti-Wild-Type Adeno-Associated Virus Type 2 (AAV2) Antibodies Inhibit Recombinant AAV2 (rAAV2)-Mediated, but Not rAAV5-Mediated, Gene Transfer in the Brain.
C. S. Peden, C. Burger, N. Muzyczka, and R. J. Mandel (2004)
J. Virol.
78, 6344-6359
|Abstract »|Full Text »|PDF »
The subthalamic nucleus in the context of movement disorders.
C. Hamani, J. A. Saint-Cyr, J. Fraser, M. Kaplitt, and A. M. Lozano (2004)
Brain
127, 4-20
|Abstract »|Full Text »|PDF »
Neuroprotection by caffeine and more specific A2A receptor antagonists in animal models of Parkinson's disease.
M. A. Schwarzschild, K. Xu, E. Oztas, J. P. Petzer, K. Castagnoli, N. Castagnoli Jr., and J.-F. Chen (2003)
Neurology
61, S55-61
|Abstract »|Full Text »
Gene Transfer to the Nervous System: Prospects for Novel Treatments Directed at Diseases of the Aging Nervous System.
M. Mata, J. C. Glorioso, and D. J. Fink (2003)
J Gerontol A Biol Sci Med Sci
58, M1111-M1118
|Abstract »|Full Text »|PDF »
Diet supplements and gene therapy tried for Parkinson's disease.
