The Neuronal Stress Response in Neurodegenerative Disease and Pain
- Claire E. Le Pichon, PhD, Head, Unit on the Development of Neurodegeneration
- Hanna Silberberg, MA, Biologist
- Li Chen, PhD, Postdoctoral Visiting Fellow
- Jorge Gomez Deza, PhD, Postdoctoral Visiting Fellow
- Caroline Donahue, BA, Postbaccalaureate Fellow
- Jacob M. Gluski, BA, Postbaccalaureate Fellow
- Josette J. Wlaschin, MSc, Postbaccalaureate Fellow
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 [References 1 & 2]. The lab is currently investigating how such diverse diseases converge upon this single 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 [Reference 2]. The most exciting implication of this study is that DLK is an important driver of neurodegeneration with diverse etiologies, suggesting it is part of a long sought common mechanism of neurodegeneration and is thus an attractive therapeutic target.
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. 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 now focusing, in parallel, on two key questions: understanding how DLK performs these dual roles; and determining how distinct diseases converge upon this common pathway.
DLK is required for microgliosis and pain after traumatic injury to sensory neurons.
I have had a long-term interest in neurodegeneration and the involvement of DLK. After working at Genentech and prior to starting at NICHD, in the course of two years spent working semi-independently at the NINDS, and in collaboration with the Chesler and Hoon labs, my work in the field of somatosensation and pain resulted in several co-authorships [e.g., References 3 & 4]. The work led to the idea of examining 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 pain, raising the tantalizing possibility that inhibition of DLK would also be an effective treatment for pain [Reference 1].
Partial sciatic nerve axotomy results in the development of mechanical hypersensitivity (allodynia), which can be measured by a reflexive paw withdrawal response. We demonstrated that DLK deletion blocks the development of this mechanical allodynia by preventing the full complement of transcriptional changes that normally occur following injury. Strikingly, 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 data corroborate recent work from others showing that neuronal expression of Csf1 after injury is required for the spinal cord microgliosis and necessary for the development of the mechanical allodynia (Guan et al., Nat Neurosci 2016;19:94).
Nerve injury initiates a cascade of events that evolve over time as pain becomes chronic. We therefore examined a time course of acute transcriptional changes in the dorsal root ganglion (DRG) for key genes, which we found to correlate with the onset of microgliosis. Knowing the time course of gene expression changes aided design of a study in which we examined the protective effects of a pharmacological DLK inhibitor after nerve injury. Importantly, inhibitor treatment between 18 hours and 8 days post-injury was sufficient to suppress DLK–dependent transcriptional changes and spinal cord microgliosis and to prevent mechanical pain. The results expose DLK as a critical regulator of events leading from nerve injury to the development of neuropathic pain and suggest that targeting this pathway might be of therapeutic value. They also highlight non-cell autonomous aspects of the neuronal injury response, for example an injured neuron-to-microglia signal that has interesting implications in the context of neurodegeneration, and in which neuroinflammation is thought to be a key player.
Additional Funding
- DDIR Innovation Award
Publications
- Wlaschin JJ, Gluski JM, Nguyen E, Silberberg H, Thompson JH, Chesler AT, Le Pichon CE. Dual leucine zipper kinase is required for mechanical allodynia and microgliosis after nerve injury. eLife 2018;7:e33910.
- Le Pichon CE, Meilandt WJ, Dominguez S, Solanoy H, Lin H, Ngu H, Gogineni A, Sengupta Ghosh A, Jiang Z, Lee SH, Maloney J, Gandham VD, Pozniak CD, Wang B, Lee S, Siu M, Patel S, Modrusan Z, Liu X, Rudhard Y, Baca M, Gustafson A, Kaminker J, Carano RAD, Huang EJ, Foreman O, Weimer R, Scearce-Levie K, Lewcock JW. Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease. Sci Transl Med 2017;9:403.
- Ghitani N, Barik A, Szczot M, Thompson JH, Li C, Le Pichon CE, Krashes MJ, Chesler AT. Specialized mechanosensory nociceptors mediating rapid responses to hair pull. Neuron 2017;95:944-954.
- Szczot M, Pogorzala LA, Solinski HJ, Young L, Yee P, Le Pichon CE, Chesler AT, Hoon MA. Cell-type-specific splicing of Piezo2 regulates mechanotransduction. Cell Reports 2017;21(10):2760-2771.
Collaborators
- Alexander Chesler, PhD, Sensory Cells and Circuits Section, NCCIH, Bethesda, MD
- Mark Hoon, PhD, Laboratory of Sensory Biology, NIDCR, Bethesda, MD
- Nicholas Ryba, PhD, Laboratory of Sensory Biology, NIDCR, Bethesda, MD
Contact
For more information, email claire.lepichon@nih.gov or visit http://lepichon.nichd.nih.gov.
