From Axon Damage to Disease: Common Pathways in Neurodegeneration
- 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
- Sangeetha Hareendran, PhD, Postdoctoral Visiting Fellow
- Leana Ramos, BA, Postbaccalaureate Fellow
- Mor Alkaslasi, BS, Graduate Student
- Zoe Piccus, MA, Graduate Student
- Josette J. Wlaschin, MSc, Graduate Student
Our work is dedicated to a better understanding of common molecular and cellular mechanisms of neurodegeneration, with the ultimate goal of developing treatments for neuro-degenerative diseases and even preventing them. The lab currently focuses on an evolutionarily conserved neuronal stress-response pathway under the 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 such 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 3 & 4]. The lab is currently investigating how such diverse diseases converge upon this single pathway and how this pathway mediates divergent fates.
Motor neuron identity in health and disease
Our most recent publication concerns collaborative work with the lab of Nick Ryba, in which we perform single-nucleus RNA sequencing of sensory neurons with or without nerve injury, and examine neuron fate on an individual cell basis [Reference 2]. We found that nerve injury induces profound transcriptional reprogramming in sensory neurons that normally exist in many different types and that, upon injury, lose their original identity and switch to a completely novel, injured neuronal identity. We also found that sensory neurons have the potential to recover, returning to their native transcriptional state.
In parallel work, the lab is now investigating whether the same holds true for skeletal motor neurons, and if not, in what ways such neurons differ in their injury response. The work is relevant to motor neuron diseases of many kinds, in which it is thought that specific subtypes are more vulnerable to disease than others. We began with a description of the motor neuron types that exist, given that, although the existence of many subtypes was known, their diversity overall and the best markers were not known. This year, we produced an atlas of cholinergic neurons of the adult mouse spinal cord [Reference 1]. The work is currently in revision for Nature Communications. We will follow up by studying the disease state and investigating whether motor neurons undergo transcriptional reprogramming similar to the sensory neurons after nerve injury and what happens to these cells over the long term, after acute nerve injuries and also in disease models.
Using the neuronal injury response to study neurodegeneration in the mammalian CNS
The existence of common mechanisms of neurodegeneration has long been hypothesized. My previous work 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. The work uncovered an important role for DLK signaling in promoting neuronal death as well as controlling synapse density, using several different animal models of neurodegeneration. We also showed that human disease tissue bears markers of DLK/JNK signaling activation [Reference 4]. 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.
In new work, we generated a reporter mouse line that we named Stress-TRAP, which expresses Cre to permanently label neurons that have engaged in injury signaling, so as to visualize, track, enrich for, and study injured neurons in the context of acute injury models (e.g., nerve injury, traumatic brain injury) or neurodegenerative diseases caused by inherited mutations. We will use these mouse lines to perform single-cell sequencing studies, as well as whole cleared brain imaging, in which we selectively labeled the neurons undergoing injury signaling. Especially at early stages of disease, we anticipate the tool will be of great use in detecting the earliest neuronal pathologies, when the affected neurons are still quite sparse.
Additional Funding
- NICHD SD Award 2020
- ALS Association Milton Safenowitz Postdoctoral Fellowship (2019) to Dr. Jorge Gomez-Deza, ongoing
- Intramural AIDS Research Fellowship 2020 to Mor Alkaslasi
Publications
- Alkaslasi MR, Piccus ZE, Silberberg H, Chen L, Zhang Y, Petros TJ, Le Pichon CE. Single nucleus RNA-sequencing defines unexpected diversity of cholinergic neuron types in the adult mouse spinal cord. bioRxiv 2020;193292.
- Nguyen MQ, Le Pichon CE, Ryba N. Stereotyped transcriptomic transformation of somatosensory neurons in response to injury. eLife 2019;8:e49679.
- 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.
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
- Teresa Dunn-Giroux, PhD, Uniformed Services University of the Health Sciences, Bethesda, MD
- Tracey Rouault, MD, Section on Human Iron Metabolism, NICHD, 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.
