RESUMO
PPARγ is a ligand-activated nuclear receptor best known for its involvement in adipogenesis and glucose homeostasis. PPARγ activity has also been associated with neuroprotection in different neurological disorders, but the mechanisms involved in PPARγ effects in the nervous system are still unknown. Here we describe a new functional role for PPARγ in neuronal responses to injury. We found both PPAR transcripts and protein within sensory axons and observed an increase in PPARγ protein levels after sciatic nerve crush. This was correlated with increased retrograde transport of PPARγ after injury, increased association of PPARγ with the molecular motor dynein, and increased nuclear accumulation of PPARγ in cell bodies of sensory neurons. Furthermore, PPARγ antagonists attenuated the response of sensory neurons to sciatic nerve injury, and inhibited axonal growth of both sensory and cortical neurons in culture. Thus, axonal PPARγ is involved in neuronal injury responses required for axonal regeneration. Since PPARγ is a major molecular target of the thiazolidinedione (TZD) class of drugs used in the treatment of type II diabetes, several pharmaceutical agents with acceptable safety profiles in humans are available. Our findings provide motivation and rationale for the evaluation of such agents for efficacy in central and peripheral nerve injuries.
Assuntos
Axônios/metabolismo , Regulação da Expressão Gênica/fisiologia , Regeneração Nervosa/fisiologia , Neurônios/patologia , PPAR gama/metabolismo , Neuropatia Ciática/patologia , Anilidas/farmacologia , Animais , Axônios/efeitos dos fármacos , Axotomia , Células Cultivadas , Embrião de Mamíferos , Gânglios Espinais/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas de Neurofilamentos/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Signalling by the p75 neurotrophin receptor has been implicated in diverse neuronal responses, including increased differentiation or survival, inhibition of regeneration, and initiation of apoptotic cell death. These numerous roles are matched by, but are not yet correlated with, a multiplicity of extracellular ligands and intracellular interactors. Membrane proteins such as sortilin, a member of the Vps10p family of sorting receptors, and the glycosylphosphatidylinositol-linked Nogo receptor (NgR) and the associated adaptor lingo 1 have recently been added to the list of p75-interacting modulators. Other studies have described intramembranal cleavage of p75 and the potential nuclear targeting of cleavage fragments or of the complete receptor after it has been internalized into a putative signalling endosome. These findings suggest that some of the diversity in p75 activities might be due to differential subcellular localization and transport of p75 receptor complexes. We therefore argue that cell-biology-driven approaches are now required to make sense of p75 signalling.