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D1 and D2 receptors agonists can induce dyskinesia in the MPTP-
lesioned monkey [ 19 , 20 ], D2 receptors are traditionally regarded
as being less involved than D1 receptors. In MPTP monkeys
with LID, striatal overexpression of RGS9-2, a guanosine triphos-
phatase (GTPase) protein that inhibits D2 receptor downstream
signaling—achieved by viral vector injection into the striatum—
diminishes the involuntary movement intensity without lessening
the antiparkinsonian effects of L -DOPA. In contrast, in these ani-
mals, striatal RGS9-2 overexpression diminishes both the involun-
tary movement intensity and the antiparkinsonian effects of the
D2/D3 receptor agonist ropinirole [ 21 ].
In addition to dopamine receptors, the synaptic scaffolding pro-
tein PSD-95, which organizes ionotropic glutamate receptors and
their associated signaling proteins, has been shown to be overex-
pressed in LID [ 22 ]. As PSD-95 also interact with D1 receptor traf-
fi cking and function, it has been suggested that, the downregulation
of PSD-95 levels could decrease the severity of LID by releasing D1
receptor membrane anchorage. Such hypothesis has been tested in a
nonhuman primate model using LV-mediated PSD-95 downex-
pression. In dyskinetic monkeys, the disruption of D1 receptors and
PSD-95 through lowering striatal PSD-95 levels alleviates dyskine-
sia severity [ 3 ], which indicates that altering D1 receptor traffi cking
via synapse-associated scaffolding proteins may be useful in the
treatment of dyskinesia in PD patients. This LV vector gene therapy
strategy, hoping to abolish the dyskinesia severity, was also investi-
gated with success at the level of the ERK cascade. Instead of directly
modulating the ERK expression, the targeting of RasGRF1, a stria-
tum- and neuron-specifi c activator of Ras proteins, which couples
the ERK cascade to both glutamatergic (NMDA) and dopaminergic
(D1) receptors, was preferred. In MPTP-lesioned macaque, the
intrastriatal delivery of an LV dominant-negative construct of Ras-
GRF1, leading to a reduction of Ras-GRF1 expression, has been
shown to attenuate the severity of established LID [ 19 ].
LV vector gene therapy was not only studied at the level of PD
but also for the development of genetic model of Huntington's
disease (HD) in NHP. Palfi and coworkers have investigated the
possible relationships between mechanisms that are specifi cally
triggered by overexpression mutated huntingtin protein (htt) and
behavioral defi cits. The bilateral injection of mutant htt in the lat-
eral putamen was associated with the appearance of spontaneous
dyskinesia of the legs, arms, and trunk as early as week 15 postin-
fection [ 23 ] providing a proof of principle for the development of
genetic models of HD in NHPs.
Taking these results together, lentiviral vectors open new
opportunities to treat neurological disorders. With its larger
cloning capacity, LV appears to be not only a useful tool to create
genetic models including in NPH but also provides new opportu-
nity to assess motor symptoms and to perform preclinical studies.
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