Parkinson Therapies Go Deep and Shallow

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

Comments

  1. The new paper by Lo Bianco et al. marks a significant addition to their work with α-synuclein vectors and a breakthrough as the first example of an effective treatment against neurodegeneration evoked by viral vectors carrying toxic genes. Though several treatments have been shown to counteract neurotoxin lesioning, and some have been developed for Parkinson disease trials, none of them, including delivery of GDNF—as this group has shown in previous studies—has been reported to be effective in such vector models. Lo Bianco et al. now show that lentiviral delivery of parkin can have therapeutic value. These viral vector models of disease are new and we can expect that they will play an important role in selecting agents for human trials in the future.

    The increase in hyperphosphorylated aggregates in the parkin-treated animals is intriguing, although confirmation of the microscopic analysis with Western blots would have been even more convincing. It remains unclear if the neuroprotective action of parkin is related to its ubiquitin ligase activity, or if the effect of parkin is specific for α-synuclein. In this regard, we are currently testing parkin against mutant tau gene transfer, which results in behaviorally significant substantia nigra degeneration (submitted manuscript).

    View all comments by Richard Zweig

  2. This elegant paper extends observations previously made in tissue culture (Petrucelli et al., 2002; Oluwatosin-Chigbu et al., 2003; Chung et al., 2004) and Drosophila (Yang et al., 2003; Haywood and Stavely, 2004) models of α-synuclein toxicity, namely that parkin can suppress neuronal damage. There are several advantages to the model used by Lo Bianco et al. Here, lentiviruses are used to deliver a chronic, in vivo exposure to α-synuclein that this group has previously shown to induce selective nigral degeneration in a vertebrate animal. Therefore, it is gratifying to see that the experiment first performed in vitro has now worked in this more stringent, and hopefully, more physiologically relevant context.

    However, I think there are several valid concerns about the interpretation of all of these results (especially including our own work!). The major issue is that the mechanism involved is not yet clarified. Assuming we accept that parkin does affect α-synuclein toxicity, why does it do so? Parkin is known to be a ubiquitin-protein ligase, so one would assume that this E3 activity is required for protection. Several of the in vivo studies have skipped this important control, presumably to reduce the experimental complexity and associated cost. But I think this is a mistake—if the neuroprotective action is unrelated to E3 ligase function, then it probably isn’t related to human disease. One would be concerned if any E3-ligase had the same effect, or if it related to overexpression rather than physiological function. This could be addressed by using negative controls of inactive parkin.

    An important aspect of the model used by Lo Bianco is that these rats form α-synuclein positive intracellular inclusions that are presumably related to Lewy pathology. Perhaps surprisingly, the expression of parkin enhances the formation of these pathologies. This observation implies that inclusion body formation is beneficial and that by shunting α-synuclein into sequestered compartments, the cell can reduce its toxicity as suggested elsewhere (e.g., Olanow et al., 2004). However, it has been argued that space-filling lesions are also likely to be damaging to neurons over time (see Giasson and Lee, 2003, for a critical discussion of this issue). The significance of the model used by Lo Bianco et al. is that it gives us a way to tackle some really difficult problems. What aggregation state of α-synuclein is toxic? And is parkin disease related to PD at all or is it merely one route amongst many by which nigral neurons can die?

    References:

    Chung KK, Thomas B, Li X, Pletnikova O, Troncoso JC, Marsh L, Dawson VL, Dawson TM. S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function. Science. 2004 May 28;304(5675):1328-31. PubMed.

    Haywood AF, Staveley BE. Parkin counteracts symptoms in a Drosophila model of Parkinson's disease. BMC Neurosci. 2004 Apr 16;5:14. PubMed.

    Olanow CW, Perl DP, DeMartino GN, McNaught KS. Lewy-body formation is an aggresome-related process: a hypothesis. Lancet Neurol. 2004 Aug;3(8):496-503. PubMed.

    Oluwatosin-Chigbu Y, Robbins A, Scott CW, Arriza JL, Reid JD, Zysk JR. Parkin suppresses wild-type alpha-synuclein-induced toxicity in SHSY-5Y cells. Biochem Biophys Res Commun. 2003 Sep 26;309(3):679-84. PubMed.

    Petrucelli L, O'Farrell C, Lockhart PJ, Baptista M, Kehoe K, Vink L, Choi P, Wolozin B, Farrer M, Hardy J, Cookson MR. Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron. 2002 Dec 19;36(6):1007-19. PubMed.

    Schlossmacher MG, Frosch MP, Gai WP, Medina M, Sharma N, Forno L, Ochiishi T, Shimura H, Sharon R, Hattori N, Langston JW, Mizuno Y, Hyman BT, Selkoe DJ, Kosik KS. Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies. Am J Pathol. 2002 May;160(5):1655-67. PubMed.

    Yang Y, Nishimura I, Imai Y, Takahashi R, Lu B. Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila. Neuron. 2003 Mar 27;37(6):911-24. PubMed.

    View all comments by Mark Cookson

Make a Comment

To make a comment you must login or register.

References

News Citations

  1. Viral Transgenic Techniques Pay Off In Parkinson's Models
  2. Viral Transgene Models Parkinson's in Primate

Paper Citations

  1. Lo Bianco C, Ridet JL, Schneider BL, Deglon N, Aebischer P. alpha -Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson's disease. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10813-8. PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. 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 alpha-synuclein rat model of Parkinson's disease. Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17510-5. PubMed.
  2. Drouot X, Oshino S, Jarraya B, Besret L, Kishima H, Remy P, Dauguet J, Lefaucheur JP, Dollé F, Condé F, Bottlaender M, Peschanski M, Kéravel 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. PubMed.

Annotate

To make an annotation you must Login or Register.