Chapter 9 - p11 Gene Therapy as a Novel Target for Treatment of Symptoms and Medication Complications in Parkinson’s Disease

Abstract

Dopamine (DA) replacement therapy remains the most common treatment for symptomatic management of Parkinson’s disease (PD). Effective medications that enhance DA signaling often cause abnormal involuntary movements (AIMs), also called dyskinesias, which can be difficult to resolve without worsening PD symptoms. We recently reported that p11, a small protein necessary for neurotransmitter receptor function, is critical to DA responses in a mouse model of PD with dyskinesia. Here, we discuss these findings in view of the current understanding of mechanisms and circuit changes involved in AIMs. Blocking p11 production in the dorsal striatum, a brain region which responds to DA and regulates movement, can improve forced movements and normalize spontaneous movements in parkinsonian mice, while dramatically reducing AIMs following DA replacement therapy. Our data identify a potential target for the development of novel therapeutic approaches to both improving motor symptoms and reducing drug-related side effects in human PD.