Axonal PPAR promotes neuronal regeneration after injury

PPAR is a ligand-activated nuclear receptor best known for its involvement in adipogenesis and glucose homeostasis. PPAR activity has also been associated with neuroprotection in different neurological disorders, but the mechanisms involved in PPAR effects in the nervous system are still unknown. Here we describe a new functional role for PPAR in neuronal responses to injury. We found both PPAR transcripts and protein within sensory axons and observed an increase in PPAR protein levels after sciatic nerve crush. This was correlated with increased retrograde transport of PPAR after injury, increased association of PPAR with the molecular motor dynein, and increased nuclear accumulation of PPAR in cell bodies of sensory neurons. Furthermore, PPAR 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 PPAR is involved in neuronal injury responses required for axonal regeneration. Since PPAR 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. (c) 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 688-701, 2016