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
- Leana Ramos, BA, Postbaccalaureate Fellow
- Josette J. Wlaschin, MSc, Postbaccalaureate Fellow
- Zoe Piccus, MA, Graduate Student
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 account for only 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, also known as 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 my previous work at Genentech, I focused on DLK, a MAP3 kinase (mitogen activated protein triple kinase) that had been known, upon injury, to initiate a retrograde stress-signaling cascade from the axon to the cell body. Using several different animal models of neurodegeneration, the work uncovered an important role for DLK signaling in promoting neuronal death as well as in controlling synapse density. We also showed that human disease tissue bears markers of activation of the DLK/JNK N-terminal kinase signaling pathway [Reference 2]. The most exciting implication of this study is that DLK is part of a long-sought common mechanism of neurodegeneration, which has led to its becoming a promising drug target for the treatment of several diseases.
Intriguingly, and at first glance perhaps counter-intuitively, DLK signaling can result in many different outcomes, including neuronal death, long-term survival, and even regeneration, 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 as well as 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. The 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.
Perhaps rather unsurprisingly, peripheral nerve injury activates many transcripts downstream of DLK. However, the possibility of links between injury, DLK, and neuropathic pain had not previously been examined. Notably, work in the lab established that DLK signaling plays a causative role in neuropathic pain, raising the tantalizing possibility that DLK inhibition could 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 the 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 the 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 Z, et al. Nat Neurosci 2016;19:94-101).
Nerve injury initiates a cascade of events that evolve over time as pain becomes chronic. Our 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 may be of therapeutic value. They also highlight non-cell-autonomous aspects of the neuronal injury response, for example as a signal from injured neurons to microglia that has important implications for neurodevelopmental as well as neurodegenerative diseases and that we intend to pursue in future work.
Our most recent publication is collaborative work with the lab of Nick Ryba, in which we performed single-nucleus RNA sequencing of sensory neurons with or without nerve injury, and examined neuron fate on an individual cell basis [Reference 3]. Central findings from the work include that, firstly, nerve injury induces a profound transcriptional switch from sensory neurons of different subtypes to a completely novel, injured neuronal identity. Secondly, sensory neurons have the potential to recover, back to their native transcriptional state. Ongoing work will examine the specific contributions of injured as well as of intact neurons to the development of neuropathic pain.
Additional Funding
- DDIR Innovation Award (2019): Mechanisms of neuropathic pain
- ALS Association Milton Safenowitz Postdoctoral Fellowship (2019) to Dr. Jorge Gomez-Deza, ongoing
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.
- Nguyen MQ, Le Pichon CE, Ryba N. Stereotyped transcriptomic transformation of somatosensory neurons in response to injury. eLife 2019;8:e49679.
Collaborators
- Carsten Bönnemann, MD, Neuromuscular and Neurogenetic Disorders of Childhood Section, NINDS, Bethesda, MD
- 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
- Michael E. Ward, MD, PhD, Inherited Neurodegenerative Diseases Unit, NINDS, Bethesda, MD
Contact
For more information, email claire.lepichon@nih.gov or visit http://lepichon.nichd.nih.gov.
