The neuronal stress response in neurodegenerative disease and pain

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

We have recently shown that DLK/JNK signaling becomes activated in multiple animal models of neurodegenerative disease, and that deleting DLK or inhibiting it is protective and can delay, and even in some cases reverse, disease progression (Le Pichon et al., 2017). The mouse models examined in this study included the SOD1(G93A) model of amyotrophic lateral sclerosis (ALS), and two mouse lines that model aspects of Alzheimers disease (AD), a PS2APP model and the Tau(P301L) model. We also correlated these findings with evidence of DLK/JNK signaling in human tissue of ALS and AD patients. Despite these diseases being characterized by very distinct genetic and pathological features, loss of DLK signaling appeared to protect neurons in both types of models. This work strongly suggested that DLK signaling is a pathway common to at least several distinct neurodegenerative diseases, that can potentially act as an integrator of neuronal stress signaling. Previous work had shown that DLK is a neuronally-enriched kinase and an upstream regulator of the well-studied JNK (c-Jun N-terminal kinase) signaling pathway. The function of DLK is critical for healthy developmental neurodegeneration as well as for an appropriate response to acute nerve injury. Given that the DLK response appears to be a feature common to so many different contexts and diseases, we aim to understand the mechanism(s) by which DLK activation occurs, especially in pathological settings of chronic disease. We also seek to better understand the events downstream of DLK. For example, DLK signaling directs the transcriptional activation of genes associated with both degeneration and regeneration. What determines the ultimate outcome for the neuron, and does this response vary from cell to cell, or within a given neuron over time? Finally, if DLK is a true integrator of cellular stress, how does it fit in relative to these other stress pathways?