Molecular and cellular mechanisms of neuronal damage caused by anticancer therapies

Project Summary Cancer is a terrifying diagnosis, especially in a child, yet thanks to great advances in treatment, survival rates have increased steeply. For CNS/brain tumors and leukemias, which together account for the majority of pedi- atric cancers, these positive clinical outcomes generally require the use of CNS radiotherapy (RT). However, RT

causes significant long-term neurocognitive sequelae impacting not only cancer survivors, but also their caregi- ver networks and society. Since RT is a scheduled ‘injury’, pretreatment is feasible, but the unclear nature of RT- induced cognitive injury is a major obstacle to doing so. Research addressing RT-mediated cognitive deficits has

focused on the dividing neuroprogenitor cell (NPC) pool from which a small number of postnatal, “adult-born” neurons arises in the dentate gyrus, as the hippocampus (of which the dentate gyrus is part) is particularly RT- sensitive. While NPC damage likely contributes to cognitive decline, we and others have shown that terminally

differentiated neurons, long thought to be radioresistant, undergo marked synaptic alterations in response to RT. In this proposal, we present data showing that radiation compromises the neuronal plasma membrane, alters neuronal mitochondrial dynamics, and changes the expression of genes involved in lipid metabolism and

cholesterol biosynthesis. Moreover, we demonstrate that APOE genotype associates with post-RT cognitive outcomes in humans. These observations hearken to long-neglected studies on non-genetic loci of radiation damage that could give us critical insights into the mechanisms of RT-mediated cognitive damage. Many

questions remain unanswered, however: How and to what extent do these mechanisms of irradiative damage, including membrane permeabilization, contribute to cognitive decline? Does plasma membrane compromise affect cellular Ca2+ signaling, a known cause of aging-related cognitive decline? How are these processes affected

by the delivery of lipids from astrocytes to neurons by ApoE? What are the consequences of epigenetic changes that affect plasma membrane lipid composition? These are critical questions whose answers are required to rationally design therapies to combat RT-induced neurocognitive sequelae. We propose to use a quantitative,

multidisciplinary approach to address these issues, including: (i) determining the consequences of RT-induced plasma membrane compromise with regard to initial events and effects on mitochondrial and ER Ca2+ stores; (ii) defining the role and site of action of the lipid carrier ApoE in the neuronal response to RT, while testing the

consequences of allelic variants of ApoE and the changes in surface glutamate receptors associated therewith; and (iii) charting the nature and consequences of altered neuron lipidomes as a result of RT, including using a bioinformatics approach to identify key pathways and potential therapeutic targets. Our novel and multidisci-

plinary approach will dissect the nature of RT-mediated cognitive dysfunction at the molecular, synaptic, cellu- lar, and behavioral levels. The results of this translational proposal have the potential to greatly and positively impact the health of cancer survivors and those otherwise exposed to radiation.