Unraveling the Mechanism of Dyskinesia One Transcription Factor at a Time

Abstract

L-DOPA–induced dyskinesia (LID), or abnormal involuntary movements, is a common side effect of L-DOPA therapy in patients with Parkinson’s disease. When L-DOPA is initially administered, it effectively reverses akinesia caused by the loss of dopamine. However, long-term L-DOPA administration produces a hyperkinetic effect, triggering excessive movements in human patients and in animal models. The mechanisms of LID have been under intense investigation for decades, and numerous important discoveries in the past several years established the key mechanisms of LID development. Five dopamine receptor subtypes in the striatal neurons mediate the action of dopamine produced from L-DOPA. The main subtypes, D1 and D2, are expressed on the striatonigral and striatopallidal medium spiny neurons (MSNs), respectively, with a high degree of segregation. The relative contribution of the D1-dependent and D2-dependent signaling to LID has been hotly debated. However, findings demonstrating that genetic ablation of the D1, but not the D2, receptor abrogates LID (1) strongly suggest that the aberrant signaling via the D1 receptor is the main contributor. The striking molecular feature of the dopamine-depleted striatum is the hyperresponsiveness of multiple signaling pathways to acute dopaminergic stimulation. The D1 receptor in MSNs couples to the adenylyl cyclase–stimulating Golf, and in the dopamine-depleted striatum, the cyclic adenosine monophosphate (cAMP) response to L-DOPA is augmented, resulting in the increased activity of protein kinase A (PKA) and enhanced phosphorylation of PKA substrates. One of the substrates, the dopamine and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), upon phosphorylation by PKA at Thr34, acts as an inhibitor of protein phosphatase 1, further enhancing the activity of the cAMP-PKA cascade. Sensitized DARPP-32 contributes to LID because its genetic ablation or elimination of the PKA-phosphorylated residue ameliorates LID (2,3). In addition, DARPP-32 inactivation significantly attenuates the extracellular signal-regulated kinase (ERK) superactivity in the dopamine-depleted striatum (2), suggesting that the elevated cAMP signaling is an important mediator of the ERK superactivity. The ERK pathway shows very strong dopamine depletion– induced supersensitivity. The dopamine-induced hyperactivation of the ERK response is confined to the striatonigral MSNs, or direct pathway MSNs (dMSNs) (1,3), and genetic ablation of the D1 receptor prevents the supersensitive ERK response (1), reinforcing the notion of the prime role of the D1 receptor signaling in LID. The neuron-specific Ras–guanine nucleotidereleasing factor 1 (Ras-GRF1), the upstream activator of Ras, implicated in LID could serve as the mechanistic connection between the D1 receptor signaling and activation of the ERK