PPARγ, a nuclear receptor involved in metabolism, confers neuroprotection in models of stroke and neurodegenerative diseases. However, to date the mechanisms of action of PPARγ in neurons has not been established.
The aim of this thesis was to study whether PPARγ participates in the mechanism of neuronal growth induced by injury and neurotrophins in peripheral and central neurons.
First, we studied the role of PPARγ during regenerative responses in peripheral nervous system. We found that PPARγ protein levels are increased in the axon after axonal injury (AI), process that increases the retrograde transport of PPARγ in axons. Concomitant, we found increased levels of PPARγ in cell bodies of sensory neurons. Furthermore, inhibition of PPARγ reduced the axonal regeneration of sensory neurons and its activation promoted axonal outgrowth in axotomized cortical neurons, suggesting that PPARγ is required for regeneration after axonal injury in both peripheral and central neurons.
We also studied whether the neurotrophin BDNF induces PPARγ expression in axons of central neurons. We found that BDNF promotes PPARγ protein expression through the activation of mTOR kinase pathway in distal axons of rat cortical neurons. We also observed accumulation of PPARγ in cell bodies in response to axonal BDNF treatment, effect that was reduced by treating the axons with mTOR and retrograde transport inhibitors. Finally, we observed that PPARγ is required for BDNF-growing effects in cortical neurons.
In summary, our results suggest that PPARγ is part of a mechanism controlling neuronal growth in response to external cues such as injury and neurotrophic stimulation in the nervous system.