The neuronal stress response in neurodegenerative disease and pain

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

Our work is dedicated to the better understanding of common molecular and cellular mechanisms of neurodegeneration, with the ultimate goal of developing treatments for neurodegenerative diseases and even preventing them. The lab currently focuses on investigating an evolutionarily conserved neuronal stress response pathway under control of DLK (dual leucine zipper kinase), which plays an important role in several neuropathologies. As a cellular stress response pathway in neurons, its function is to promote recovery from injury; however, at the same time, it can drive several types of pathologies, including peripheral neuropathies and neurodegeneration. The hypothesis driving our work is that common mechanisms are responsible for neurodegeneration during development, childhood, and aging. Most of what is currently understood about neurodegenerative disease stems from the identification of genetic linkages that are causative or predisposing, and from efforts to uncover the mechanisms underlying these linkages. However, the linkages only account for a relatively small proportion of all cases. The vast majority of cases have no established genetic etiology and therefore no clear pathway to target. An understanding of any common mechanisms involved in neurodegeneration would provide major breakthroughs for designing treatments. We showed that Dual Leucine Zipper Kinase (DLK; MAP3K12) acts as a crucial downstream node in neurodegeneration and neuropathy, two pathologies with very different causes and outcomes (Le Pichon et al., 2017; Wlaschin et al., 2018). The lab is currently investigating how such diverse diseases converge upon this pathway and how this pathway mediates divergent fates. The DLK-dependent injury response promotes neurodegeneration in the mammalian CNS. The existence of common mechanisms of neurodegeneration has long been hypothesized. In previous work, I focused on DLK, which is a MAP3 kinase (mitogen activated protein triple kinase) previously shown to initiate a retrograde stress signaling cascade from the axon to the cell body, and which has since become a promising drug target for the treatment of several diseases. As a kinase that is enriched in neurons, DLK is an attractive drug target and was identified in several screens for genes that drive neurodegeneration. Moreover, DLK is upstream of JNK (c-Jun N-terminal kinase) signaling, which itself has long been proposed as a therapeutic target for neurodegeneration, but whose specific targeting has not proved feasible. Importantly, the work uncovered a powerful role for DLK signaling in several animal models of neurodegeneration and showed that human disease tissue bears markers of DLK/JNK signaling activation (Le Pichon et al., 2017). The most exciting implication of this study is that DLK is one example of a common mechanism of neurodegeneration, a node downstream of multiple etiologies. Intriguingly, and at first glance perhaps counter-intuitively, DLK signaling can result in many different outcomes, including neuronal death and long-term survival, depending on context. Several studies have shown that DLK can promote neuron death in the CNS (central nervous system), for example after injury to the optic nerve, and during normal development (e.g. for lower motor neurons). However, DLK is also described as an important pathway for axon regeneration after neuron injury. Therefore, it is thought of as a regulator and coordinator of neuronal stress signaling, able to promote recovery or death. My lab is interested in understanding how DLK performs these dual roles and in elucidating novel functions of DLK. DLK is required for microgliosis and pain after traumatic injury to sensory neurons. In recent work, we have investigated a potential role for DLK in pain. It was clear that peripheral nerve injury activates many molecules downstream of DLK. However, the possibility of links between injury, DLK, and neuropathic pain had not been examined. Notably, work in my lab established that DLK signaling plays a causative role in chronic neuropathic pain after nerve injury, raising the possibility that inhibition of DLK would also be an effective treatment for pain (Wlaschin et al., 2018). In this work, we discovered a novel role for DLK in regulating a microglial reaction in the vicinity of injured neurons. DLK controls a distress call from injured neurons to microglia via transcriptional upregulation of the neuronal cytokine Csf1, resulting in a characteristic spinal cord microgliosis at the central terminals of the DRG neurons. The microgliosis is blocked in the DLK conditional knockout (DLK cKO). Our results highlight non-cell autonomous aspects of the neuronal injury response, for example an injured neuron-to-microglia signal that has important implications in the context of neurodegeneration, and in which neuroinflammation is thought to be a key player. Understanding how neuronal identity changes after injury. Using single nucleus sequencing, we have described the different subtypes of sensory neurons and lower motor neurons that exist in mouse (Nguyen et al., eLife 2019; Alkaslasi, Piccus et al., Nat Comms 2021). We are particularly interested in how these neurons change at the transcriptomic level after injury. In collaboration with the Ryba lab (NIDCR), we have discovered that sensory neurons take on a new and common injured identity after nerve transection. They downregulate and lose their previous and varied specializations, collapsing into a similar injured transcriptomic state, then gradually recover original identities over time as the neurons regenerate. We plan to perform similar studies to investigate the outcome for lower motor neurons of the spinal cord, and in future relate these findings to more chronic disease of motor neurons.