Dyskinesias after neural transplantation in Parkinson's disease: what do we know and what is next?

Parkinson's disease (PD) is a common chronic neurodegenerative disorder characterized by the clinical presentation of motor (tremor, rigidity and bradykinesia) and nonmotor (e.g., autonomic, mood and cognitive) symptoms. Although the aetiology and pathogenetic mechanisms that cause PD remain unknown, classical descriptions of PD pathology mainly focus on the progressive degeneration of the nigrostriatal dopamine (DA) pathway and the pathology in other brainstem, cortical and subcortical structures [1]. PD patients are given DA replacement therapy for symptomatic relief, but these drugs prove beneficial up to a point and after a few years of L-3,4-dihydroxyphenylalanine (L-DOPA) therapy, the majority of PD patients develop motor complications, including abnormal involuntary movements called L-DOPA-induced dyskinesias (LIDs) [2]. As a result of this progressive decline in the clinical course of PD, more sophisticated therapeutic management has been warranted, one of which involves transplantation of fetal ventral mesencephalic (VM) tissue in the striatum of patients with PD. Human trials with fetal VM transplantation for PD have been conducted over the past two decades on the basis of the hypothesis that if PD is caused by degeneration of the nigrostriatal DA pathway and loss of DA innervation in the striatum, then restoration of the lost DA neurons by transplantation could reverse the loss of motor function. However, open-label trials and double-blind sham surgery controlled trials yielded inconsistent results and raised controversy [3]. Although some of the PD patients who underwent transplantation showed remarkable improvement of their motor symptoms, many of them had severe adverse reactions consisting of developing troublesome involuntary movements when off their DA drugs, called off-phase, graft-induced dyskinesias (GIDs) [4-6]. Whilst the exact mechanisms underlying the development of GIDs have remained unknown and there has been no effective treatment, propose