Nature Medicine | Spoonful of Medicine

Point of no return?

Modeling Parkinson disease in animals has been very hard. The chemical models (6-OHDA and MPTP) are good to study cell replacement therapies, but not so great for pathogenesis. And the genetic models have failed to give the mouse something like true Parkinson disease — there may be alpha-synuclein aggregates or structures akin to Lewy bodies, but no cell death, or vice versa. To add to the debate, Silke Nuber and her colleagues just published in J. Neurosci. a conditional model of Parkinson in which alpha-synuclein expression can be switched off by feeding the animals doxycyclin. This is an image from the paper, showing the expression of the transgene in the two divisions of the substantia nigra of the mice.


Their key finding was that turning alpha-synuclein expression off in mice that started to show neurodegeneration and behavioral symptoms halted disease progression but did not reverse it. This is quite different to what Jose Lucas and his colleagues showed years ago in Huntington disease. In that case, turning the expression of huntingtin off did reverse the motor symptoms in mice.

Albeit interesting, one wonders about the relevance of the findings of Nuber and colleagues to true Parkinson disease. Similar to previous attempts to reproduce the disease in mice, their model was not perfect — there was neurodegeneration, but no Lewy bodies.


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