Molecular and cellular determinants of L-Dopa-induced dyskinesia in Parkinson’s Disease
Federica Servillo, Maria De Carluccio, Giulia Di Lazzaro, Federica Campanelli, Gioia Marino, Giuseppina Natale, Ada Ledonne, Mariangela Massaro Cenere, Emanuela Paldino, Daniela Di Giuda, Anna Picca, Francesco Bove, Riccardo Di Iorio, Benedetta Angeloni, Angelo Tiziano Cimmino, Giovanni Bellomo, Barbara Picconi, Anna Rita Bentivoglio, Nicola Biagio Mercuri, Lucilla Parnetti, Veronica Ghiglieri, Maria Teresa Viscomi, Paolo Calabresi
Abstract
Treatment with L-3,4-dihydroxyphenylalanine (L-Dopa) compensates for decreased striatal dopamine (DA) levels and reduces Parkinson's disease (PD) symptoms. However, during disease progression, L-Dopa-induced dyskinesia (LID) develops virtually in all PD patients, making the control of PD symptoms difficult. Thus, understanding the mechanisms underlying LID and the control of these motor abnormalities is a major issue in the care of PD patients. From experimental and clinical studies, a complex cascade of molecular and cellular events emerges, but the primary determinants of LID are still unclear. Here, with a translational approach, including four animal models and a wide cohort of PD patients, we show that striatal DA denervation is the major causal factor for the emergence of LID, while α-synuclein aggregates do not seem to play a significant role. Our data also support the concept that maladaptive basal ganglia plasticity is the main pathophysiological mechanism underlying LID.