Neuroprotektion und Neurorestauration im MPTP Modell der Parkinson Erkrankung

Abstract

Parkinson s disease (PD) is the most common neurodegenerative movement disorder of the basal ganglia and is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The glial cell line-derived neurotrophic factor (GDNF) has been identified in preclinical experiments as an important differentiation and survival factor for dopaminergic neurons of the midbrain, yet its application in clinical trials has shown inconsistent efficacy. Current gene therapies delivering neurotrophic factors via neuronal expression may not fulfil essential safety criteria for more elaborate strategies with higher dosages or younger patients. Given that neurotrophic factors are potent modulators of neuronal physiology and thus may potentially provoke unwanted side effects if present in brain areas not affected by PD, it seems preferable to restrict their impact to the immediate vicinity of the site of lesion. In this study it was investigated, whether adeno-associated virus (AAV)-5 vectors injected in low and high titre concentrations into the striatum of C57Bl/6-J mice leading to either neuronal or astrocytic production of GDNF have different effects on protective and neuroregenerative efficacy in the 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Unilateral striatal vector application resulted in delivery of bio-functional GDNF to the striatum and SN of both brain hemispheres if GDNF was expressed in neurons, indicating distribution to sites far remote from the vector application. In contrast, effects of GDNF were restricted to the injected hemisphere by expression in astrocytes. Astrocytic GDNF expression was neuroprotective at low vector dosage thus representing a safe alternative to current gene therapeutic strategies for PD. It has been claimed that higher concentrations of GDNF may also signal through receptors other than the prototypical rearranged during transfection (RET) and glycosyl phosphatidylinositol linked GDNF family (GFR)α receptors. However, using mice with a tissue-selective ablation of the gene encoding Ret (DAT-Retlx/lx mice) no alternative to an intact GDNF-RET-mediated signalling in the nigrostriatal system to awaken the protective potential of GDNF after MPTP lesion was found.