Roles of Sonic Hedgehog in the modulation of striatal nitric oxide: exploring a novel target to understand the pathogenesis of Parkinson's disease.

Abstract

The Parkinson's disease (PD) is characterized by a continuous loss of the dopaminergic neurons in the substantia nigra pars compacta (SNc) leading to dopamine depletion in the striatum. Although the processes involved in neuronal death in PD are not completely understood, abundant evidences indicate that the toxic action of nitric oxide (NO) and dysfunction of neurotrophic factors play an important role in the context of dopaminergic degeneration. The morphogen Sonic Hedgehog (Shh) pathway is critical for normal growth and in addition to its role in embryonic development, it has been shown that the Shh network can participate in cell differentiation, proliferation and angiogenesis in the adults. Also, in vivo and in vitro studies have suggested that Shh may have a therapeutic value in neurodegenerative disease. Recently study demonstrated that the interruption of Shh signaling originating from dopaminergic neurons of the SNc recapitules key features of the progressive cellular neurochemical and functional pathologies observed in PD. In the striatum, a subpopulation of NO positive neurons expresses the Hedgehog interacting protein (Hip), natural antagonist of Shh family, raising the possibility of a functional relationship between Hedgehog signaling and NO. The aim of this study is to investigate the mechanistic role of Shh and its natural antagonist, Hip on the biochemical activation of striatal NO. Our hypothesis is that in the absence of Shh, Hip can interacts with the pathways involved in the production of NO. To address this question, we will perform a battery of in vivo and in vitro modulations of Shh signaling and measure the expression of Shh, Hip and NO at mRNA and protein levels. Motor behavioral tests will also be performed. The ultimate goal of our studies is to provide new insight into the mechanisms that lead to the degenerative process in PD and open new therapeutic interventions that either slow or halt these processes.