Thwarting Dyskinesia by Targeting mTORC1
Eric Klann (21 July 2009)
Science Signaling 2 (80), pe42. [DOI: 10.1126/scisignal.280pe42]

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PERSPECTIVE
NEUROSCIENCE

Thwarting Dyskinesia by Targeting
mTORC1
Eric KlannPublished 21 July 2009; Volume 2 Issue 80 pe42

In a mouse model of Parkinson’s disease, new evidence shows that L-DOPA,
which is used to treat the symptoms of the disease but also causes dyskinesia,
results in a persistent activation of the protein kinase mTOR (mammalian targetof rapamycin) in a subset of striatal medium spiny neurons. Moreover, blockadeof a specific type of mTOR signaling (mTORC1) prevents the development ofdyskinesia, but not the antiakinetic benefits produced by L -DOPA. Thus,
mTORC1 may be a viable therapeutic target for dyskinesia caused by L-DOPA
treatment in patients with Parkinson’s disease.

Center for Neural Science, New York University, New York, NY 10003, USA. E-mail, eklann@
cns.nyu.edu

tive approach for preventing dyskinesia
caused by L-DOPA.
In the hippocampus, long-lasting
synaptic plasticity requires not only ERK
but also the mammalian target of rapamycin (mTOR), a protein kinase that is
intimately involved in the initiation oftranslation when in a complex with Raptor (regulatory associated protein ofmTOR) (6, 7); this complex is termed
mTORC1. ERK is required for mTORC1
signaling in protein synthesis–dependent
forms of long-term potentiation (8, 9) andconverges with mTORC1 signaling in
regulating protein synthesis–dependent,
metabotropic glutamate receptor–dependent long-term depression (10). Thus,
ERK and mTORC1 are both required forlong-lasting synaptic plasticity.
Because L-DOPA–induced dyskinesia
has been associated with persistent ERK
activation and enhancements in striatal
synaptic plasticity (11), Santini et al.
posited that mTORC1 might be one of thedownstream effectors of ERK requiredfor dyskinesia. The authors lesioned mice
unilaterally with 6-hydroxydopamine (6OHDA), a toxin often used to induce
Parkinsonian symptoms in rodents. In
biochemical experiments, the authors
showed that administration of L-DOPA to
6-OHDA–lesioned mice increased striatal
phosphorylation of two mTORC1 substrates, p70 S6 kinase (S6K) and initiation factor 4E–binding protein (4E-BP),both of which are involved in stimulatingtranslation initiation (6, 7), as well as ribosomal protein S6, a substrate of S6K.
The L -DOPA–induced increase in thephosphorylation of mTORC1 substrates
was blocked by inhibition of ERK signaling. In addition, the L-DOPA–induced increases in S6K and S6 phosphorylation in

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One of the difficulties in treating any disease, including those of the nervous system, is that even effective treatments canresult in severe side effects. For example,
currently the most effective treatment for
Parkinson’s disease is L-DOPA. Unfortunately, in addition to its antiakinetic properties, L-DOPA causes multiple motor alterations, including dyskinesia (unwantedspasmodic movements). Thus, it would bevery desirable to prevent dyskinesia without negating the antiakinetic benefits provided by L-DOPA for Parkinson’s disease
patients. Santini et al. (1) describe a series of experiments that begin to address
this problem.
Parkinson’s disease is caused by theloss of dopaminergic neurons in the substantia nigra that project to the striatum.
This loss of nigrostriatal neurons resultsin alterations in intracellular signaling inmedium spiny neurons (MSNs) when
they are exposed to dopaminergic drugs,
including L -DOPA. One key signaling
molecule that is activated in MSNs in response to L -DOPA is extracellular signal–regulated kinase (ERK) (2), an intensely studied protein kinase that is acore component required for multiple
types of synaptic plasticity (3). L-DOPA
triggers persistent activation of ERK inMSNs, which is required for dyskinesia(4). However, ERK is a “hub” moleculein signaling pathways, integrating diverse
cellular signals and dispersing them to a
multitude of downstream effectors, thereby making it a problematic drug target(5). Thus, targeting specific downstream
effectors of ERK might be a more effec-

the striatum were blocked by a dopamine
D1 receptor antagonist but not by a D2
receptor antagonist. Taken together, thesefindings indicate that D1 receptors and
ERK are required for L -DOPA–induced
activation of mTORC1 in a mouse modelof Parkinson’s disease (Fig. 1).
To identify the striatal MSNs in which
the L-DOPA–induced increase mTORC1
signaling occurred, the authors performed
an elegant set of experiments using immunocytochemistry with transgenic miceexpressing enhanced green fluorescentprotein (EGFP) under the control of thepromoter for either the D1 receptor or theD2 receptor. They found that L-DOPA increased S6 phosphorylation in the MSNs
that contain D1 receptors, but not thosethat contain D2 receptors. Moreover, increased phosphorylation of ERK, whichis required for its activation, colocalizedwith increased phosphorylation of S6 after L -DOPA treatment. These f indings
suggest that mTORC1 signaling is increased in the same D1-containing MSNs
that contain increased ERK in response toL-DOPA treatment.
Santini et al. then addressed the critical question: Can inhibition of mTORC1
prevent L -DOPA–induced dyskinesia inmice that model Parkinson’s disease?
Mice were lesioned with 6-OHDA andtreated with L -DOPA for 9 days alongwith either vehicle or the mTORC1 inhibitor rapamycin, which prevents mTOR
from binding to Raptor (12). L -DOPA
treatment increased mTORC1 signaling,which was prevented in the mice treatedwith rapamycin. Moreover, mice thatwere treated with L -DOPA and vehicle
displayed robust dyskinesia, whereas
mice that were treated with L-DOPA andrapamycin had a large reduction in these
involuntary movements. Finally, to address whether rapamycin also inhibitedthe beneficial effects of L -DOPA treatment in the Parkinson’s disease model
mice, the authors conducted a cylinder
test and found that rapamycin did not alter the ability of L-DOPA to prevent forelimb akinesia produced by the 6-OHDAlesion.
The array of approaches used by Santiniet al. provided numerous independent lines
of evidence consistent with the idea thatmTORC1 signaling is necessary for L DOPA–induced dyskinesia in Parkinson’s
disease model mice. First, they conducted
the “measure” experiment (13) to directly
test whether mTORC1 signaling occurred

PERSPECTIVE

in association with the dyskinesia. Using
biochemical and immunocytochemical approaches, they found enhanced phosphorylation of mTORC1 substrates and their effectors. Next, using an elegant approachcombining D1 EGFP transgenic mice andimmunocytochemistry, the authors showedthat the increased mTORC1 signaling occurred in D1 receptor–containing MSNs ofthe direct pathway. The authors proceeded
to conduct the critical “block” experiment(13) and found that rapamycin blocked LDOPA–induced dyskinesia, demonstratingthat the activation of mTORC1 was functionally relevant for this behavior.
It would be of great interest if a “mimic” experiment (13) could be done todemonstrate that increasing mTORC1
activity in D1-containing MSNs could
induce dyskinesia inthe 6-OHDA modelof Parkinson’s disease. One potential
way to conduct thistype of mimic experiment would bewith floxed FK506binding protein 12(FKBP12) mice. It
has been shown thatbrain-specific deletion of FKBP12, a
putative endogenousinhibitor of mTORC1,
results in increased
mTORC1 signaling(14). Strikingly, the FKBP12 mutant micedisplayed an increase in repetitive behavior, which suggests that increased
mTORC1 signaling might alter striatal
plasticity and behavior. Thus, the specificdeletion of FKBP12 in D1-containing
MSNs might mimic the effect of L-DOPAin 6-OHDA–lesioned mice.
Rapamycin and its derivatives are currently being tested as a treatment for patients with cancer (15), and other classes ofmTORC1 inhibitors are in development(16). This is of particular interest because
rapamycin did not reduce the L-DOPA–induced increases in the phosphorylation of
the individual mTORC1 substrates and theireffectors to the same extent. Moreover,mTOR can also exist in a complex withRictor (rapamycin-insensitive companion ofmTOR) termed mTORC2, which regulates
the cytoskeleton and phosphorylates Akt(17, 18). Although mTORC2 was originallyreported to be rapamycin-insensitive (17),subsequent findings indicated that prolonged rapamycin treatment can inhibit
mTORC2 formation and Akt (19). Thus, itis possible that the ability of rapamycin toprevent L -DOPA–induced dyskinesia in
6-OHDA–lesioned mice is through inhibition of mTORC2 and Akt. Nonetheless,
mTORC1 inhibitors such as rapamycin havethe potential to be a viable therapy to treat
Parkinson’s disease patients with dyskinesia
caused by long-term L-DOPA treatment.
Using an impressive multidisciplinary
experimental approach, Santini et al. provide a strong argument that mTORC1 signaling in D1-containing MSNs in thestriatum is a critical component of L DOPA–induced dyskinesia in Parkinson’s
disease. These results demonstrate for the
first time that translational control in thestriatum is altered in response to L-DOPA
treatment and further confirm the generalrole of mTORC1 in long-lasting changes
in behavior.
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Fig. 1. Proposed mechanism for mTORC1-dependent dyskinesia after L-DOPA treatment in Parkinson’s disease. Treatment with LDOPA triggers the D1 receptor (D1R)–mediated activation of ERK
via Golf–adnenylyl cyclase–cAMP–protein kinase A (PKA) signalingin MSNs of the nigrostriatal direct pathway. ERK activates mTORC1either by phosphorylating and activating PDK1/2 (3-phosphoinositide–dependent protein kinase 1 or 2) (9) or by phosphorylating andinactivating TSC2 (tuberous sclerosis 2) (20). Deactivation of theTSC1-TSC2 complex results in the activation of Rheb andmTORC1, resulting in the phosphorylation of 4E-BP and S6K. The
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initiation. Newly synthesized proteins, as yet unidentified, thencause dyskinesia. Rapamycin bound to FKBP12 disrupts mTORC1,
thereby preventing the synthesis of new proteins and, subsequently,
dyskinesia caused by L-DOPA.

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10.1126/scisignal.280pe42

Citation: E. Klann, Thwarting dyskinesia by targeting mTORC1. Sci. Signal. 2, pe42 (2009).

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