Chemotherapy with anti-microtubule agents is often accompanied by peripheral neuropathy, a side effect which limits the dose and duration of chemotherapy. A promising approach to ameliorate peripheral neuropathy is to augment nicotinic acid dinucleotide (NAD) in axons. NAD is an enzymatic cofactor that has recently been shown to protect axons from degeneration elicited by a wide range of chemotherapeutic agents and other toxic insults. For example, treatment with NAD markedly delays and reduces sensory axon degeneration elicited by vinca alkaloids, such as vinblastine and vincristine, which are commonly used in cancer chemotherapy. Additionally, axons in WldS mice, which express a chimeric protein that catalyzes NAD biosynthesis, are markedly resistant to anti-microtubule agents. These in vitro and in vivo studies demonstrate the potential impact of the NAD-regulated axonoprotective pathway on developing strategies to overcome chemotherapy-induced peripheral neuropathy. However, it is not known how to take advantage of the beneficial effects of NAD since it is not clear how to increase NAD in axons. This is due to our lack of understanding of NAD metabolism in neurons. We have found evidence for novel role for Schwann cells, which ensheath axons, in delivering NAD precursors to axons. Our data suggest that Schwann cells metabolize the NAD precursor nicotinic acid into an intermediate that is transferred to axons for final conversion into NAD.
In Aim 1, we will identify this metabolite and test whether Schwann cells are required for augmenting NAD levels in in vivo models of vinca alkaloid-induced peripheral neuropathy.
In Aim 2, we will identify a ubiquitin ligase that function to degrade NAD biosynthetic machinery in axons. This enzyme accounts for NAD deficiency in axons after various types of axonal injuries and insults. We will establish whether knockdown of this enzyme reduces the susceptibility of axons to vinca alkaloid-induced axonal degeneration. Together, the experiments described in this proposal will identify novel mechanisms that control NAD levels in axons, and will provide novel avenues for therapeutic intervention for chemotherapy- induced peripheral neuropathy.
Nicotinamide adenine dinucleotide (NAD) exerts a powerful protective effect against peripheral neuropathy induced by anti-microtubule agents used in chemotherapy, but our understanding of how to exploit this for therapeutic approaches is limited. In this application, we examine the mechanism by which the NAD precursor nicotinic acid is metabolized and transferred to axons, and we characterize an enzyme whose inhibition is predicted to markedly enhance NAD levels in axons. Together, the experiments proposed in this application will provide an avenue for future therapeutic development towards treating or preventing peripheral neuropathy associated with anti-microtubule agents.
|Harkcom, William T; Ghosh, Ananda K; Sung, Matthew S et al. (2014) NAD+ and SIRT3 control microtubule dynamics and reduce susceptibility to antimicrotubule agents. Proc Natl Acad Sci U S A 111:E2443-52|