Serotonin neurons cause graft dyskinesias

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Marios Politis (Imperial College London, first author), Paola Piccini (last author), David Brooks, Niall Quinn and colleagues, with Anders Björklund, Olle Lindvall and Stig Rehncrona, who ran the original grafts in Lund. Science Translational Medicine 2(38):38ra46, June 2010. Funders were not read.

What happened

Some people who received fetal dopamine-cell grafts (landmark 3) later developed "graft-induced dyskinesias": involuntary writhing movements that continue even when off levodopa.

• PET scans of two patients who got grafts of fetal midbrain tissue in the mid-1990s (Alzforum) showed excess serotonin nerve endings in the grafted striatum. Their serotonin-to-dopamine neuron ratio was two to four times above normal (Alzforum). Dopamine neuron survival and dopamine production were normal.
• Buspirone (a 5-HT1A receptor agonist, which dampens serotonin release) markedly reduced the dyskinesias. Alzforum reports three doses at 30-minute intervals and relief of about four hours. No worsening of Parkinson's symptoms was read from the source.

Why it moved us toward a cure

It explained the main side effect that troubled grafts in landmark 3 and made purity of the graft a design goal. Modern stem-cell products are made to be dopamine-specific for this reason.

Outcome

Advanced. The finding came from two patients. Curt Freed, whose group has done over 60 transplants, told Alzforum he disagreed: in his patients the dyskinesias reflected too much dopamine activity, and he suggested testing buspirone in people with drug-induced dyskinesias who had no graft. Europe PMC lists no correction or retraction. The exact interval since grafting was not stated in the sources read.

Sources

• Politis et al., "Serotonergic neurons mediate dyskinesia side effects in Parkinson's patients with neural transplants," Sci Transl Med 2010;2(38):38ra46, DOI 10.1126/scitranslmed.3000976, PMID 20592420 (abstract via Europe PMC); details from Alzforum, "Serotonin Neurons: Culprits in Graft-Related Parkinson Dyskinesia"
• Not yet verified: the original paper's full text (the 30 June date and the numbers marked Alzforum are not in the abstract); later trials of buspirone for these dyskinesias.