Mitochondrial dysfunction in the striatum: Implications for L-DOPA Induced Dyskinesia

Abstract

L-DOPA Induced Dyskinesia (LID) is the motor complication involving an overproduction of movement that arises from L-DOPA treatment of Parkinson's disease (PD). Despite the high incidence of the development of LID, the etiology of this side effect and variability in its speed of onset is still poorly understood. Previous work in the lab discovered that subjects with PD who had developed LID had less striatal mitochondrial DNA (mtDNA), relative to non-dyskinetic PD and healthy subjects. The focus of this research was thus to identify mechanisms by which reduced mtDNA might affect the function of the striatal neurons typically affected by LID. Through treating primary murine striatal cultures with low doses of ethidium bromide (EtBr) to selectively inhibit mtDNA replication and transcription, it was determined that mtDNA reduction reduces mitochondrial respiration in neurons and astrocytes, but selectively increases glycolytic activity in astrocytes. Further, decreased mtDNA selectively reduces the expression of mitochondrial creatine kinase in neurons, which is accompanied by a reduction in phosphocreatine quantity. Creatine and phosphocreatine act as crucial energy distributing molecules to facilitate the transfer of mitochondrially-synthesized ATP-phosphates to other sites of high energy demand in the cytosol. Consequently, reduced phosphocreatine production, arising from reduced mtDNA, may impair efficient energy transfer in the striatum. This may contribute to the development of maladaptive signaling pathways associated with LID.