Mechanisms regulating neuronal degeneration and repair

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

Investigators

Linked publications, trials & patents

Abstract

The Le Pichon lab investigates the cellular and molecular mechanisms of neuronal degeneration and repair. Our goal is to understanding pathways that control the degeneration and resilience of neurons in disease. Devastating neurodegenerative diseases are highly prevalent yet there are almost no effective treatments available. To develop therapies, it is essential to uncover the pathways by which neurons become dysfunctional and die. The research in my lab centers on uncovering fundamental principles governing neuronal degeneration. Our goal is to learn how to repair and protect these cells after injury and during disease. Focus area 1 – Injury responses in neurons and basic mechanisms of neurodegeneration Diverse neurodegenerative diseases converge on common cellular programs that govern neuronal fate. Understanding and suppressing the downstream programs directing neurodegeneration offers a powerful approach to prevent neuronal degeneration and death. The first area of focus in the lab is to uncover basic mechanisms underlying these programs. These fall under two categories, signaling mechanisms and transcription-dependent mechanisms. 1a. Novel mechanisms of DLK signaling In previous work, we showed that dual leucine zipper kinase (DLK or Map3k12) is an essential regulator of neurodegeneration and that its genetic ablation or pharmacological inhibition is protective in multiple animal models of neurodegenerative disease. To further elucidate mechanisms of how DLK regulates axon degeneration and neuronal death, we have examined its role in human neurons using live imaging and defined a novel mechanism by which DLK drives axon degeneration. We find that DLK can initiate an apoptotic cascade of mitochondrial fission in the axon after injury. Using live confocal imaging of human axons, upon an injury to the axon, DLK sets off a wave of apoptotic mitochondrial fission that travels from the damage site back to the cell body, leading to axon degeneration and neuronal cell death. The retrograde mitochondrial fission requires DLK-dependent phosphorylation of the GTPase dynamin related peptide 1 DRP1. • Gómez-Deza J, Nebiyou M, Alkaslasi MR, Nadal-Nicolás FM, Somasundaram P, Slavutsky AL, Li W, Ward ME, Watkins TA, Le Pichon CE. DLK-dependent axonal mitochondrial fission drives degeneration after axotomy DLK-dependent axonal mitochondrial fission drives degeneration after axotomy Nat Commun 15, 10806 (2024). PMID 39737939 • Gómez-Deza J, Nebiyou M, El Touny LH, Alkaslasi MR, Zuo Z, Wlaschin JJ, Nadal-Nicolas FM, Slavutsky AL, Lloyd EYH, Hayashi PM, Ashby N, Sohn M, Dale R, Li W, Cheng KC, Rocha PP, Le Pichon CE. ATF2 phosphorylation is a core transcriptional driver of neuron apoptosis. bioRxiv [Preprint]. 2025 May 8:2023.09.27.559856. doi: 10.1101/2023.09.27.559856.PMID: 40654834 1b. The role of transcriptional reprogramming in neurons undergoing stress responses To examine whether neurons of the central nervous system (CNS) exhibit transcriptional reprogramming after traumatic injury, we characterized a model of concussion and investigated whether transcriptomic plasticity occurs in the CNS, as is well described in the peripheral nervous system. We find that cortical neurons do not undergo the broad transcriptional reprogramming observed in the PNS, but that Atf3 is upregulated in a population of neurons, a subset of which undergoes DLK-dependent death. • Alkaslasi MR, Lloyd EYH, Gable AS, Silberberg H, Yarur HE, Tsai VS, Sohn M, Margolin G, Tejeda HA, Le Pichon CE. The transcriptional response of cortical neurons to concussion reveals divergent fates after injury. Nat Commun 16, 1097 (2025). PMID 39870620 Focus area 2 – Development of motor neuron pathology in ALS 2a. Pre-symptomatic disease in existing mouse models of motor neuron disease A second approach to elucidating fundamental disease mechanisms in neurodegeneration is to better understand presymptomatic stages of disease. This work will hopefully lead to developing methods for early detection and identifying targets for intervention. We focus much of our work on motor neurons (MNs) as a highly tractable cell type for gaining a broad understanding of the pathophysiology of neurodegeneration. Taking advantage of our expertise with mouse models we are probing presymptomatic disease stages that are impossible to examine in patients. This work combines single cell transcriptomics with anatomical and physiological data to identify transcriptional nodes that confer vulnerability or resiliency to MNs. 2b. Development of mouse models of motor neuron disease derived from mutations in SPTLC1 Newly identified mutations in SPTLC1 and related genes implicate sphingolipid biogenesis pathways in motor neuron disease. To enable research into this area, we have generated mice harboring mutations knocked into the endogenous mouse Sptlc1 gene and are characterizing their pathology. 2c. Development of therapeutic approaches to treat ALS In collaborative work, we are developing ways to treat diseased neurons in ALS. 97% of ALS cases and 50% of FTD cases exhibit TDP-43 pathology, meaning that TDP-43 protein is mislocalized from the nucleus of affected cells and often aggregates in the cytoplasm. This leads to pathologies related to the dual loss and gain of function of TDP-43 including many alterations in RNA splicing, proper gene expression, and proteostasis. This recent publication shows a proof of concept method for a gene therapy in which transgene expression relies on nuclear loss of TDP-43, such that only diseased cells express the transgene. This method would avoid the potential toxicity of expressing a therapy in healthy cells and specifically target those that lack nuclear TDP-43 function. • Wilkins OG, Chien MZYJ, Wlaschin JJ, Barattucci S, Harley P, Mattedi F, Mehta PR, Pisliakova M, Ryadnov E, Keuss MJ, Thompson D, Digby H, Knez L, Simkin RL, Diaz JA, Zanovello M, Brown AL, Darbey A, Karda R, Fisher EMC, Cunningham TJ, Le Pichon CE, Ule J, Fratta P. Creation of de novo cryptic splicing for ALS and FTD precision medicine. Science. 2024 Oct 4;386(6717):61-69. PMID: 39361759; PMCID: PMC7616720.