Failure of Diphtheria Toxin Model to Induce Parkinson-Like Behavior in Mice.

Lucie Valek,Irmgard Tegeder

doi:10.3390/ijms22179496

Lucie Valek, Irmgard Tegeder

Open Access

https://doi.org/10.3390/ijms22179496

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Abstract

Rodent models of Parkinson’s disease are based on transgenic expression of mutant synuclein, deletion of PD genes, injections of MPTP or rotenone, or seeding of synuclein fibrils. The models show histopathologic features of PD such as Lewi bodies but mostly only subtle in vivo manifestations or systemic toxicity. The models only partly mimic a predominant loss of dopaminergic neurons in the substantia nigra. We therefore generated mice that express the transgenic diphtheria toxin receptor (DTR) specifically in DA neurons by crossing DAT-Cre mice with Rosa26 loxP-STOP-loxP DTR mice. After defining a well-tolerated DTx dose, DAT-DTR and DTR-flfl controls were subjected to non-toxic DTx treatment (5 × 100 pg/g) and subsequent histology and behavioral tests. DAT protein levels were reduced in the midbrain, and tyrosine hydroxylase-positive neurons were reduced in the substantia nigra, whereas the pan-neuronal marker NeuN was not affected. Despite the promising histologic results, there was no difference in motor function tests or open field behavior. These are tests in which double mutant Pink1−/−SNCAA53T Parkinson mice show behavioral abnormalities. Higher doses of DTx were toxic in both groups. The data suggest that DTx treatment in mice with Cre/loxP-driven DAT-DTR expression leads to partial ablation of DA-neurons but without PD-reminiscent behavioral correlates.

Highlights

A number of rodent models of Parkinson’s disease based on human genetics of PD have been described [1], and have been extensively studied in terms of behavior, mostly motor functions and PD-like histopathology [2,3]
The data suggest that diphtheria toxin (DTx) treatment in mice with Cre/loxP-driven DAT-diphtheria toxin receptor (DTR) expression leads to partial ablation of DA-neurons but without PD-reminiscent behavioral correlates
We show in the present study that DTx injections in mice were very toxic at doses used in previous studies targeting peripheral cells, glia or neurons of the central and peripheral nervous system

Summary

Introduction

A number of rodent models of Parkinson’s disease based on human genetics of PD have been described [1], and have been extensively studied in terms of behavior, mostly motor functions and PD-like histopathology [2,3]. Behavioral studies of non-motor manifestations such as cognition, olfaction, anxiety-like behavior and gastrointestinal functions are fragmented. The majority of genetic PD rodents carry human mutant alpha synuclein (SNCA) [4,5], which causes early onset dominant PD in humans. Transgenic mutant LRRK2 models have been introduced to study late onset dominant or sporadic PD [10]. While histology revealed synuclein aggregates in aged to old mice in genetic PD models, motor manifestations were mostly subtle [6,7,8,9,10]

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Discussion

Conclusion