8 December 2004. Two articles from the past week describe very different approaches to therapy for Parkinson disease (PD). A paper published 2 December in PNAS went close to the root of the problem, reporting that overexpression of parkin from cDNA delivered by a viral vector can prevent degeneration of dopamine neurons in an α-synuclein model of the disease. Meanwhile, in a paper published the same day in Neuron, researchers describe the use of motor cortex stimulation to ameliorate movement symptoms in a toxin-induced model of PD.
Patrick Aebischer and Christophe Lo Bianco of the Swiss Federal Institute of Technology in Lausanne led a multinational team that explored the interplay of parkin and α-synuclein, as well as the role of α-synuclein aggregations in the pathology of Parkinson disease. Their disease model (see Lo Bianco et al., 2002), similar to that introduced several years ago by two other research teams (see ARF related news story), involves injecting a lentiviral vector containing cDNA for disease-causing mutant α-synuclein into the substantia nigra of rats. This method results in the degeneration of the dopamine neurons in this region. It has subsequently been developed for primates as well (see ARF related news story).
In the present experiments, Lo Bianco and colleagues added a virus driving overexpression of normal parkin, which has proven to be neuroprotective in a number of studies. Lentiviral vectors with A30P human α-synuclein and/or rat parkin were injected into the substantia nigra on one side of the brain. The contralateral SN served as a control. The researchers found that the number of dopaminergic cells had decreased by 30 percent in the injected SN, relative to the control side, six weeks following α-synuclein transduction, but decreased by only nine percent when parkin was cotransduced (P < 0.005). A marker of dopaminergic terminals in the striatum revealed similar benefits from parkin overexpression, as did silver staining for degenerating neurons in SN.
Interestingly, these benefits were achieved without reductions in phosphorylated α-synuclein inclusions in the SN dopaminergic neurons. Parkin overexpression actually increased the number of phosphorylated aggregates in α-synuclein-transfected SN neurons by 45 percent (P < 0.05). These results bear directly upon the ongoing debate about the role of Lewy bodies in Parkinson disease, and, indeed, the roles of abnormal protein aggregates in other neurodegenerative diseases. Aebischer's group and others have advanced the notion that α-synuclein-containing aggregates, at least those containing hyperphosphorylated protein, are neuroprotective. Taking into account their current results, the authors hypothesize that "parkin helps dopamine neurons survive by promoting the sequestration of toxic prefibrillar oligomers in mature hyperphosphorylated inclusions."
The other study published last week aims for symptomatic treatment of movement symptoms in PD. Stéphane Palfi and colleagues at the Henri Mondor Hospital in Créteil, as well as several other institutions in France, are working on stimulation technology that might avoid the need to implant electrodes deep into the brain (deep brain stimulation, or DBS) in order to compensate for lost SN neural activity. Because the primary motor cortex is intimately linked with the activity of subcortical movement circuits in complex feedback loops, the authors decided to try noninvasive stimulation of this cortical area in baboons.
First author Xavier Drouot and colleagues created a PD model by progressively lesioning SN dopaminergic neurons with the toxin MPTP. During the 52-week course of toxin exposure, the baboons developed akinsia (decrease of movement initiation) and bradykinesia (decrease of movement velocity), along with a gradual drop in dopamine in the striatum, the target of SN projection neurons. The authors found that low-voltage, high-frequency motor cortex stimulation (MCS) with an electrode under the skull, but outside the dura mater, significantly reduced both akinesia and bradykinesia, with benefits increasing as disability became worse. PET imaging studies revealed that in severely debilitated baboons, the cortical stimulation increased activity in the supplementary motor area, a secondary cortical motor region, and normalized measures of neural activity in subcortical circuits.
"Whether MCS can be as efficient as [subthalamic nucleus] or [globus pallidus internal segment] electrical stimulation to alleviate motor symptoms in PD patients is a question that will require specifically designed comparative clinical trials. Nevertheless, the results obtained here in baboons strongly suggest that this may be the case," write the authors. The fact that there was no evidence of cell loss or inflammation in response to the stimulation in this study should enhance the chances of such trials.—Hakon Heimer.
Lo Bianco C, Schneider BL, Bauer M, Sajadi A, Brice A, Iwatsubo T, Aebischer P. Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an α-synuclein rat model of Parkinson's disease. Proc Natl Acad Sci U S A. 2004 Dec 2; [Epub ahead of print] Abstract
Drouot X, Oshino S, Jarraya B, Besret L, Kishima H, Remy P, Dauguet J, Lefaucheur JP, Dolle F, Conde F, Bottlaender M, Peschanski M, Keravel Y, Hantraye P, Palfi S. Functional recovery in a primate model of Parkinson's disease following motor cortex stimulation. Neuron. 2004 Dec 2;44(5):769-78. Abstract