Using adenoviral vectors to study the pathophysiology of Parkinson ´s disease.

F.J. PITOSSI

Workshop; 2do. SIMPOSIO FRANCO-ARGENTINO DE NEUROCIENCIAS; 2012

Using adenoviral vectors to study the pathophysiology of Parkinson ´s disease. Fernando J. Pitossi Leloir Foundation, CONICET, Buenos Aires. Argentina. One patho-physiological feature consistently found in animal models and PD patients is robust microglial activation. However, microglia activation could mediate neurodegenerative or neuroprotective effects depending on the array of molecules associated with this activation and the molecular and cellular context in which they act. As a consequence, microglial activation remains an unreliable therapeutic target in PD treatment. We believe that identifying parameters that could determine a univocal role of microglial activation on neuronal cell death in the substantia nigra (SN), the main region affected in PD, is crucial to define new therapeutic targets against PD and select PD patients to be enrolled in anti-PD trials based on immunomodulation. We have found that microglial activation in the degenerating SN is “primed”. Microglial cells can be shifted to a pro-inflammatory state by, not only central, but also sub toxic levels of systemic inflammation. This shift can dramatically exacerbate on-going neurodegeneration in the SN leading to increased and earlier motor symptoms, via Interleukin-1beta (IL-1) overproduction. In addition, we have observed that sustained but not acute expression of IL-1 or Tumor necrosis factor-alpha (TNF) in the SN leads to dopaminergic neuronal demise, motor symptoms and microglial activation. TNF effects are dose-dependent since, using a combination of knock-in mice, adenoviral vectors and the CRE/lox system we could demonstrate that low levels of TNF can be neuroprotective for nigral neurons, while higher levels could be detrimental. In conclusion, we have identified parameters that determine a given effect of pro-inflammatory cytokines on neuronal viability, paving the way to test new hypothesis, study the effects of immunomodulatory treatments, and identify downstream effector molecules on these newly generated models of PD.