Potentiation of in vivo neuroprotection by BclXL and GDNF co-expression depends on post-lesion time in deafferentiated CNS neurons

Abstract

To elucidate effective and long-lasting neuroprotective strategies, we analysed a combination of mitochondrial protection and neurotrophic support in two well-defined animal models of neurodegeneration, traumatic lesion of optic nerve and complete 6-hydroxydopamine (6-OHDA) lesion of nigrostriatal pathway. Neuroprotection by BclX L , Glial cell line-derived neurotrophic factor (GDNF) or BclX L plus GDNF co-expression were studied at 2 weeks and at 6-8 weeks after lesions. In both lesion paradigms, the efficacy of this combination approach significantly differed depending on post-lesion time. We show that BclX L expression is more important for neuronal survival in the early phase after lesions, whereas GDNF-mediated neuroprotection becomes more prominent in the advanced state of neurodegeneration. BclX L expression was not sufficient to finally inhibit degeneration of deafferentiated central nervous system neurons. Long-lasting GDNF-mediated neuroprotection depended on BclX L co-expression in the traumatic lesion paradigm, but was independent of BclX L in the 6-OHDA lesion model. The results demonstrate that neuroprotection studies in animal models of neurodegenerative diseases should generally be performed over extended periods of time in order to reveal the actual potency of a therapeutic approach. Gene Therapy (2006) 13, 1569-1578.

The mechanism of sirtuin 2–mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease

“…Both female and male WT and SIRT2-KO mice were used for AAV injections. All surgical procedures, intracerebral stereotaxic vector injections into the right hemisphere SNpc (coordinates were as follows: AP: –3.2; ML: –1.2; DV: –4.4 mm relative to Bregma, tooth bar: 0.0 mm), and tissue preparations were performed essentially as described [46]. Mice were injected with 2 μL of control GFP or human WT aSyn AAV6 virus (~1x10 8 vg/ml) into the right SN at a flow rate of 0.2 μl/min.…”

Sumoylation inhibits α-synuclein aggregation and toxicity

“…All experimental animal procedures were performed according to experimental licenses issued by the responsible animal welfare authority of Niedersächsisches Landesamt für Verbraucherschutz und Lebensmittelsicherheit and controlled by the local animal welfare committee of the University of Göttingen. Intracerebral stereotaxic injections into SN of 2.5-mo-old female Wistar rats, sacrifice, and perfusion were performed essentially as previously described (Shevtsova et al, 2006). In brief, vector injections into SNpc were performed using a Kopf stereotaxic device with a computer-controlled microinjector pump (Word Precision Instruments).…”

Aggregation of αSynuclein promotes progressive in vivo neurotoxicity in adult rat dopaminergic neurons

“…All surgical procedures, intracerebral stereotaxic vector injections into the left hemisphere SNpc (coordinates were AP: −5.3; ML: +2.2; DV: −7.7 mm, relative to bregma) and tissue preparations were performed as described [37]. Young adult female Wistar rats (250–280 g) were injected with a total of 2 μl containing 1.2 × 10 8 transducing units.…”