Status message

We are currently rebuilding the search index. Some search results may be inaccurate or incomplete.

. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1325-30. PubMed.

Recommends

Please login to recommend the paper.

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

  1. This paper supports the longstanding hypothesis that mitochondrial derangements are sufficient to cause cell death in nigral neurons, which may be an important clue for Parkinson disease. There is some later cell loss in the ventral tegmental area, which differs from Parkinson disease and from other models, and presumably if Tfam had been knocked out in other neurons, as well, one might see loss in other brain regions. We cannot quite conclude from these experiments alone that mitochondrial damage is sufficient to cause PD. But when added to the emerging evidence from genetic parkinsonism, where mitochondrial function is also implicated, the results suggest that mitochondrial function is important for maintenance of neuronal function and survival.

    These mice obviously have great potential utility in testing therapies aimed at preventing the symptoms of PD. Ekstrand et al. show that the mice respond to the major (symptomatic) therapy available for PD, that is, L-dopa. It is very interesting to see that there is an aging component to the responsiveness to L-dopa, which might be important for other therapies in the future. Also interesting is the observation of inclusion bodies in the dying cells. Showing how careful a study this is, Ekstrand et al. prove that these are not α-synuclein-positive despite one polyclonal antibody to synuclein labeling them. Presumably, the inclusion bodies are related to mitochondria, which might be a very novel part of the inclusion body formation process and worth pursuing in the future.

  2. This is a very interesting paper. It clearly shows that select loss of mitochondrial function in midbrain dopaminergic neurons can lead to a progressive respiratory chain deficiency, which then leads to inclusion formation and loss of dopaminergic neurons. The study is very well done. The authors have characterized the mice behaviorally. They have shown motor deficits, which respond to L-dopa therapy. The progressive development of the loss of midbrain neurons had several of the key features of PD. It showed adult-onset neurodegeneration, slowly progressive clinical course, earlier onset of cell death, and more extensive cell death in the substantia nigra than the ventral tegmental area, as well as the development of inclusions. The inclusions proved not to be α-synuclein-positive. They contained mitochondrial proteins as well as membrane components.

    The strength of this is that it is a slowly evolving model of PD. It also ties in to recently observed marked increases in mitochondrial deletions in the substantia nigra, which occur in laser-dissected individual dopaminergic neurons of PD patients (Bender et al., 2006). The increase in deletions in these neurons is sufficient to cause cell death in other circumstances. The present findings, therefore, support these observations as being of pathophysiologic importance in both normal aging and in the pathogenesis of PD. The increase in deletions in the human patients may be a consequence of oxidative stress related to dopamine turnover.

    The one caveat I have about the present paper is that the group created the mitochondrial dysfunction specifically in dopamine neurons only. It would have been interesting to determine if the same thing occurs in other neurons, or with a more generalized mitochondrial dysfunction of brain, and whether this would result in a relatively selective vulnerability of dopaminergic neurons. Nevertheless, this model will be highly useful for testing a number of therapeutic interventions.

    References:

    . High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nat Genet. 2006 May;38(5):515-7. PubMed.

This paper appears in the following:

News

  1. New Mouse Model Links Mitochondria to Parkinson Disease