National Institutes of Health

Eunice Kennedy Shriver National Institute of Child Health and Human Development

2017 Annual Report of the Division of Intramural Research

The Neuronal Stress Response in Neurodegenerative Disease and Pain

Claire Le Pichon
  • Claire E. Le Pichon, PhD, Head, Unit on the Development of Neurodegeneration
  • Hanna Silberberg, MA, Biologist
  • Jacob M. Gluski, BA, Postbaccalaureate Intramural Research Training Award Fellow

The launching point for our research is the dual leucine zipper kinase (DLK, also known as Map3k12), which is a critical regulator of the neuronal stress response to injury. Although the DLK stress response has been more extensively studied in the context of neuronal development as well as acute physical injury, such as nerve crush, we found that it also becomes activated in mouse models of neurodegenerative disease. DLK signaling directs a transcriptional program allowing the neuron to respond to the insult, which can manifest as degeneration as well as regeneration, depending on the context. We study DLK activation in mouse models of neurodegeneration as well as in acute surgical models, such as sciatic nerve injury. Our overall goal is to better understand (1) the mechanisms of DLK activation in disease, (2) the factors influencing degenerative versus regenerative outcomes, and (3) how the DLK pathway correlates with other pathways of cellular stress.

We recently showed that DLK/JNK signaling becomes activated in several 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 (Reference 1). 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 Alzheimer's 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. Although these diseases are 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 and 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 a better understanding of the events downstream of DLK. For example, DLK signaling directs the transcriptional activation of genes associated with both degeneration and regeneration. We wish to determine what determines the ultimate outcome for the neuron, whether this response varies from cell to cell, or within a given neuron over time, whether DLK is a true integrator of cellular stress, and how it correlates with these other stress pathways.

Additional Funding

  • DDIR Innovation Award

Publications

  1. 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.
  2. 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.
  3. Chesler AT, Szczot M, Bharucha-Goebel D, Ceko M, Donkervoort S, Laubacher C, Hayes LH, Alter K, Zampieri C, Stanley C, Innes AM, Mah JK, Grosmann CM, Bradley N, Nguyen D, Foley AR, Le Pichon CE, Bönnemann CG. The role of PIEZO2 in human mechanosensation. New Engl J Med 2016 375:1355-1364.
  4. Lee SH, Le Pichon CE, Adolfsson O, Gafner V, Pihlgren M, Lin H, Solanoy H, Brendza R, Ngu H, Foreman O, Chan R, Ernst JA, DiCara D, Hotzel I, Srinivasan K, Hansen DV, Atwal J, Lu Y, Bumbaca D, Pfeifer A, Watts RJ, Muhs A, Scearce-Levie K, Ayalon G. Antibody-mediated targeting of tau in vivo does not require effector function and microglial engagement. Cell Rep 2016 16(6):1690-1700.

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.

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