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Modeling clinical features of neurodegeneration

Nature Medicine volume 16, page 1372 (2010)Cite this article

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To the Editor:

In basic Parkinson's disease research, one major obstacle is that animal models and in vitro studies do not recapitulate features or incorporate mechanisms associated with the onset of Parkinson's disease. Animal models rarely take into account essential clinical characteristics of Parkinson's disease such as the age of onset, the focal onset of clinical features, limited pathology (cell loss is initially restricted to substantia nigra dopaminergic neurons and the presupplementary motor area), the slow progression, and the appearance of clinical signs beyond the classic triad of tremor, bradykinesia and rigidity. Indeed, degeneration of the substantia nigra might occur naturally only in humans, which would imply that the selective vulnerability of these dopaminergic cells is a unique feature of our development and functional connectivity. If so, animal models using toxins or transgenically overexpressed proteins are invoking mechanisms that do not mimic pathologically relevant disease triggers in humans. The same could be said for in vitro studies, where, despite attempts to model alterations in specific cellular components (such as the proteasome, lysosome and mitochondria), the relevance of these processes to disease pathogenesis remains disputable. For instance, labeling of Lewy bodies or Lewy-like inclusions is a common feature of Parkinson's disease, but real Lewy bodies have not been seen in any animal or in cell culture. Thus, efforts should be focused on developing etiologically relevant models that closely mimic clinical features of Parkinson's disease. Further basic research would also benefit from the use of tissue and cell lines from affected individuals and human controls to identify relevant pathogenic mechanisms. Although research into specific defects in a fundamental signaling pathway may guide development of neuroprotective therapies for neurodegenerative diseases, to my mind, the feasibility of this approach is remote if the approach to modeling pathogenesis of disease does not take into account clinically relevant features.

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  1. Department of Neurology, Clínica Universitaria and Medical School of Navarra, Neuroscience Centre, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain

    José A Obeso

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  1. José A Obeso
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Correspondence to José A Obeso.

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Obeso, J. Modeling clinical features of neurodegeneration. Nat Med 16, 1372 (2010). https://doi.org/10.1038/nm1210-1372b

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