Panel A: AADC in one of three monkeys with focal AADC expression. One site in the caudate nucleus and 2 sites in the putamen were targeted bilaterally with focal AAV-hAADC. Panel B: AADC-transduced regions in the caudate as shown in panel A. AADC expression is restricted to medium spiny neurons. Thus, L-dopa administration (L-dopa is converted to DA by AADC-expressing cells) results in activation of dopamine receptors only within the focal region of the striatum. L-dopa administration in these NHP resulted in significant induction of dyskinesias.
The Causes of Dyskinesia
As Parkinson’s disease progresses, most if not all patients begin taking
. L-Dopa is converted to
in the brain by the enzyme,
. Over time, the potency of the drug wanes. Patients require steadily increasing amounts of Sinemet. Along with this phenomenon is the appearance of disabling involuntary movements called dyskinesia. Two-thirds of all patients develop this motor complication within several years of initiation of therapy, the most prominent of which are so-called L-dopa-induced dyskinesias (LID). Several patterns of dyskinetic movements have been identified: (i) peak-dose-dyskinesias, (ii) dysphasic-dyskinesias, and (iii) end-of-dose. There is also the phenomenon of low-dose dyskinesias that pose particular clinical and treatment difficulties. Patients with young-onset parkinsonism appear to be at the highest risk for developing debilitating dyskinesias.
Our Project
The broad aim of our project is to test the hypothesis that dyskinesias in Parkinson’s disease (PD) arise at least in part from non-uniform dopaminergic innervation of the striatum. It is possible that irregular loss of dopamine (DA) terminals within the motor-related posterior putamen results in “hotspots” of dopamine synthesis, leading to uneven patterns of neuronal activity that in turn generate abnormal dyskinetic motor output. This hypothesis is consistent with data from several groups that focal generation of DA in the posterior striatum following fetal tissue engraftment leads to a significant risk of severe medication-resistant dyskinesias in previously non-dyskinetic individuals with PD. Over a number of years, we have developed an adeno-associated virus containing the cDNA encoding aromatic L-amino acid decarboxylase (AAV2-hAADC). Transduced with this vector, striatal neurons gain the ability to produce DA from exogenous L-dopa, a dopamine precursor. We have observed severe L-dopa-induced dyskinesias (LID’s) in animals when AAV-AADC was infused into the striatum in a way that generated focal regions of high AADC activity. In contrast, diffuse expression of AADC throughout the striatum does not increase the propensity for dyskinesias. Through our ability to manipulate the anatomical distribution of striatal DA while avoiding the complexities associated with cell grafting techniques, we propose testing whether focal hotspots of DA within the posterior putamen and/or inter-regional disparities in DA availability increase the propensity for dyskinesias. This research program seeks to test important hypotheses regarding the mechanistic and anatomical origins of L-dopa-dependent dyskinesias. It also integrates behavior, neurophysiology, imaging, and anatomy in an unprecedented manner that is likely to yield significant new insights into the genesis and maintenance of one of the most serious sequelae of L-dopa therapy. This work is supported by a grant from the
NIH-NINDS.
