Q&A with Dr. Gilberto Fisone - Inhibition of mTOR prevents LID

In a new paper published today in Science Signaling, Santini et al. demonstrate that inhibition of mTOR signaling by rapamycin can prevent L-DOPA-induced dyskinesia in a PD animal model. Dr. Gilberto Fisone is the last author of this paper and discusses his latest work on mTOR, a downstream signaling protein in the Ras-ERK pathway, with Dr. Holli Kawadler of MJFF.

HK: Can you summarize your findings and the immediate next steps you feel are necessary to move this discovery further?

GF: There are two main conclusions stemming from our findings. The first one is that loss of dopamine in the striatum confers to L-DOPA the ability to promote mTOR signaling. This is important, since virtually nothing is known about the ability of dopaminergic drugs to act on this signaling cascade. This effect of L-DOPA is exerted on the medium spiny neurons which express dopamine D1 receptors and which represent about 50% of all projection neurons in the striatum.

The second conclusion is that persistent activation of mTOR signaling, such as that produced by repeated administration of L-DOPA to Parkinsonian patients, may be responsible for the development of dyskinesia. This is suggested by: 1) the association between increased phosphorylation of several components of the mTOR signaling cascade and the abnormal involuntary movements developed in a mouse model of L-DOPA-induced dyskinesia, and 2) the ability of rapamycin, the prototypical mTOR inhibitor, to attenuate this behavioral response. 

One important immediate step will be to test the effect of rapamycin and rapamycin-like drugs in a more "advanced", non-human primate model of dykinesia. It will also be important to determine whether other types drugs interacting with mTOR signaling are able to reproduce the action of rapamycin and perhaps to act more efficiently.  The considerable interest around the development of mTOR inhibitors as anti-cancer agents will certainly benefit progress in this direction.  

HK: You demonstrate administration of L-DOPA increases mTORC1 activity. How do you link activation of mTORC1 to observed L-DOPA induced dyskinesia?

GF: The results of our study indicate that administration of L-DOPA leads to activation of one of the two mTOR multiprotein complexes, named mTORC1. This complex is inhibited by rapamycin and is involved in ribosome biogenesis, protein synthesis and translation. Therefore, it will be important to determine what are the effects produced by L-DOPA, via activation of mTORC1, on the expression of specific proteins involved in the control of the state of excitability of striatal medium spiny neurons. It is possible that some of these changes may concur to the development of dyskinesia.

HK: Rapamycin is currently prescribed as an immunosuppressant and other mTOR inhibitors are being tested as anti-cancer agents for their anti-proliferative properties. What other information do we need to move mTOR inhibition forward as an anti-dyskinetic strategy?

GF: There are a few important issues that need to be addressed related to the use of rapamycin analogs for the treatment of dyskinesia. To begin with, we need more information about the distribution of mTORC1 inhibitors in the brain, following systemic administration. 

We also need to know more precise information about other types of effects produced by mTOR inhibition in the brain. For instance, it has been reported that rapamycin counteracts cognitive impairment produced by constitutive activation of mTOR signaling. In the hypothalamus, mTOR signaling is implicated in the regulation of food intake. 

It will also be necessary to examine further the effects produced by chronic administration of rapamycin. There is evidence that prolonged exposure to rapamycin leads to reduced mTOR levels, thereby affecting not only mTORC1, but also the other mTOR complex, mTORC2, which is involved in the activation of the Akt pathway. Because mTORC1 and mTORC2 exert distinct actions, which may lead to different responses, it will be important to monitor the effects exerted by mTOR inhibitors on both complexes.

Santini E, Heiman M, Greengard P, Valjent E, Fisone G. Inhibition of mTOR Signlaing in Parkinson's Disease Prevents L-DOPA-Induced Dyskinesia. Science Signaling. 2, ra36 (2009).