Neuroscience
Abstract
In Guillain-Barré syndrome (GBS), both axonal and demyelinating variants can be mediated by complement-fixing anti-GM1 ganglioside autoantibodies that target peripheral nerve axonal and Schwann cell (SC) membranes, respectively. Critically, the extent of axon degeneration in both variants dictates long-term outcome. The differing pathomechanisms underlying direct axonal injury and the secondary “bystander” axonal degeneration following SC injury are unresolved. To investigate this, we generated glycosyltransferase-disrupted transgenic mice that express GM1 ganglioside either exclusively in neurons (GalNAcT-/--Tg(neuronal)) or glia (GalNAcT-/--Tg(glial)), thereby allowing anti-GM1 antibodies to solely target GM1 in either axonal or SC membranes, respectively. Myelinated axon integrity in distal motor nerves was studied in transgenic mice exposed to anti-GM1 antibody and complement in ex vivo and in vivo injury paradigms. Axonal targeting induced catastrophic acute axonal disruption as expected. When mice with GM1 in SC membranes were targeted, acute disruption of perisynaptic glia, and SC membranes at nodes of Ranvier (NoR) occurred. Following glial injury, axon disruption at nodes also developed sub-acutely, progressing to secondary axon degeneration. These models differentiate the distinctly different axonopathic pathways under in axonal and glial membrane targeting conditions, and provide insights into primary and secondary axon injury, currently a major unsolved area in GBS research.
Authors
Rhona McGonigal, Clare I. Campbell, Jennifer A. Barrie, Denggao Yao, Madeleine E. Cunningham, Colin L. Crawford, Simon Rinaldi, Edward G. Rowan, Hugh J. Willison
Abstract
The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase known for its oncogenic potential and involved in the development of the peripheral and central nervous system. ALK receptor ligands, ALKAL1 and ALKAL2 were recently found to promote neuronal differentiation and survival. Here we show that inflammation or injury enhanced ALKAL2 expression in a subset of TRPV1+ sensory neurons. Notably, ALKAL2 was particularly enriched in both mice and human peptidergic nociceptors, yet weakly expressed in non peptidergic, large diameter myelinated neurons or in the brain. Using a co-culture expression system, we found that nociceptors exposed to ALKAL2 exhibited heightened excitability and neurite outgrowth. Intraplantar Complete Freund′s adjuvant (CFA) or intrathecal infusion of recombinant ALKAL2 led to ALK phosphorylation in the lumbar dorsal horn of the spinal cord. Finally, depletion of ALKAL2 in dorsal root ganglia or blocking ALK with clinically available compounds Crizotinib or Lorlatinib, reversed thermal hyperalgesia and mechanical allodynia induced by inflammation or nerve injury, respectively. Overall, our work uncovers the ALKAL2-ALK signaling axis as a central regulator of nociceptor-induced sensitization. We propose that clinically approved ALK inhibitors used for Non–Small Cell Lung Cancer and neuroblastomas, could be repurposed to treat persistent pain conditions.
Authors
Manon Defaye, Mircea C. Iftinca, Vinicius M. Gadotti, Lilian Basso, Nasser S. Abdullah, Melissa Cumenal, Francina Agosti, Ahmed Hassan, Robyn Flynn, Jeremy Martin, Vanessa Soubeyre, Gaëtan Poulen, Nicolas Lonjon, Florence Vachiery-Lahaye, Luc Bauchet, Pierre Francois Mery, Emmanuel Bourinet, Gerald W. Zamponi, Christophe Altier
Abstract
Charcot-Marie-Tooth disease type 1A (CMT1A), the most common inherited demyelinating peripheral neuropathy, is caused by PMP22 gene duplication. Over-expression of wild-type PMP22 in Schwann cells destabilizes the myelin sheath, leading to demyelination and ultimately to secondary axonal loss and disability. No treatments currently exist that modify the disease course. The most direct route to CMT1A therapy will involve reducing PMP22 to normal levels. To accomplish this, we developed a gene therapy strategy to reduce PMP22 using novel artificial microRNAs targeting human and mouse PMP22/Pmp22 mRNAs. Our lead therapeutic microRNA, miR871, was packaged into an AAV9 vector and delivered by lumbar intrathecal injection into C61-het mice, a model of CMT1A. AAV9-miR871 efficiently transduced Schwann cells in C61-het peripheral nerves and reduced human and mouse PMP22/Pmp22 mRNA and protein levels. Treatment at early and late stages of the disease significantly improved multiple functional outcome measures and nerve conduction velocities. Furthermore, myelin pathology in lumbar roots and femoral motor nerves was ameliorated. Treated mice also showed reductions in circulating biomarkers of CMT1A. Taken together, our data demonstrate that AAV9-miR871-driven silencing of PMP22 rescues a CMT1A model and provides proof of principle for treating CMT1A using a translatable gene therapy approach.
Authors
Marina Stavrou, Alexia Kagiava, Sarah G. Choudury, Matthew J. Jennings, Lindsay M. Wallace, Allison M. Fowler, Amanda Heslegrave, Jan Richter, Christina Tryfonos, Christina Christodoulou, Henrik Zetterberg, Rita Horvath, Scott Q. Harper, Kleopas A. Kleopa
Abstract
The encoding of noxious stimuli into action potential firing is largely mediated by nociceptive free nerve endings. Tissue inflammation, by changing the intrinsic properties of the nociceptive endings, leads to nociceptive hyperexcitability, and thus to the development of inflammatory pain. Here, we showed that tissue inflammation-induced activation of the mammalian target of rapamycin complex 2 (mTORC2) triggers changes in the architecture of nociceptive terminals and leads to inflammatory pain. Pharmacological activation of mTORC2 induced elongation and branching of nociceptor peripheral endings and caused long-lasting pain hypersensitivity. Conversely, nociceptor-specific deletion of the mTORC2 regulatory protein, Rictor, prevented inflammation-induced elongation and branching of cutaneous nociceptive fibers and attenuated inflammatory pain hypersensitivity. Computational modelling demonstrated that mTORC2-mediated structural changes in the nociceptive terminal tree are sufficient to increase the excitability of nociceptors. Targeting mTORC2 using a single injection of antisense oligonucleotide against Rictor provided long-lasting alleviation of inflammatory pain hypersensitivity. Collectively, we showed that tissue inflammation-induced activation of mTORC2 causes structural plasticity of nociceptive free nerve endings in the epidermis and inflammatory hyperalgesia, representing a therapeutic target for inflammatory pain.
Authors
Calvin Wong, Omer Barkai, Feng Wang, Carolina Thörn Pérez, Shaya Lev, Weihua Cai, Shannon Tansley, Noosha Yousefpour, Mehdi Hooshmandi, Kevin C. Lister, Mariam Latif, A. Claudio Cuello, Masha Prager-Khoutorsky, Jeffrey S. Mogil, Philippe Séguéla, Yves De Koninck, Alfredo Ribeiro-da-Silva, Alexander M. Binshtok, Arkady Khoutorsky
Abstract
Caffeine is the most consumed psychoactive substance worldwide. Strikingly, molecular pathways engaged by its regular consumption remain unclear. We herein addressed the mechanisms associated with habitual (chronic) caffeine consumption in the mouse hippocampus using untargeted orthogonal-omics techniques. Our results revealed that chronic caffeine exerts concerted pleiotropic effects in the hippocampus, at the epigenomic, proteomic and metabolomic levels. Caffeine lowers metabolic-related processes in the bulk tissue, while it induces neuronal-specific epigenetic changes at synaptic transmission/plasticity-related genes and increased experience-driven transcriptional activity. Altogether, these findings suggest that regular caffeine intake improves the signal-to-noise ratio during information encoding, in part through a fine-tuning of metabolic genes while boosting the salience of information processing during learning in neuronal circuits.
Authors
Isabel Paiva, Lucrezia Cellai, Céline Meriaux, Lauranne Poncelet, Ouada Nebie, Jean-Michel Saliou, Anne-Sophie Lacoste, Anthony Papegaey, Hervé Drobecq, Stéphanie Le Gras, Marion Schneider, Enas M. Malik, Christa E. Müller, Emilie Faivre, Kevin Carvalho, Victoria Gomez-Murcia, Didier Vieau, Bryan Thiroux, Sabiha Eddarkaoui, Thibaud Lebouvier, Estelle Schueller, Laura Tzeplaeff, Iris Grgurina, Jonathan Seguin, Jonathan Stauber, Luisa V. Lopes, Luc Buee, Valerie Buée-Scherrer, Rodrigo A. Cunha, Rima Ait-Belkacem, Nicolas Sergeant, Jean-Sébastien Annicotte, Anne-Laurence Boutillier, David Blum
Abstract
Microglia, the parenchymal tissue macrophages in the brain, surround amyloid plaques in Alzheimer’s disease (AD) but are ineffective at clearing amyloid to mitigate disease progression. Recent studies in mice indicate that microglia are exclusively derived from primitive yolk-sac hematopoiesis and self-renew without contribution from ontogenically-distinct monocytes/macrophages of definitive ‘adult’ hematopoietic origin. Using genetic fate-mapping to label cells of definitive hematopoietic-origin throughout the life-span, we discovered that circulating monocytes contribute 6% of plaque-associated macrophages in aged AD mice. Moreover, peripheral monocytes contributed to a higher fraction of macrophages in the choroid plexus, meninges and perivascular spaces of aged AD mice versus wild-type controls, indicating enrichment at potential sites for entry into the brain parenchyma. Splenectomy, which markedly reduced circulating Ly6Chi monocytes, also reduced abundance of plaque-associated macrophages of definitive-hematopoietic origin, resulting in increased amyloid plaque load. Together, these results indicate that peripherally-derived monocytes invade the brain parenchyma, targeting amyloid plaques to reduce plaque load.
Authors
Ping Yan, Ki-Wook Kim, Qingli Xiao, Xiucui Ma, Leah R. Czerniewski, Haiyan Liu, David R. Rawnsley, Yan Yan, Gwendalyn J. Randolph, Slava Epelman, Jin-Moo Lee, Abhinav Diwan
Abstract
Many neurodegenerative disorders are caused by abnormal accumulation of misfolded proteins. In spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine-expanded (polyQ-expanded) ataxin-1 (ATXN1) causes neuronal toxicity. Lowering total ATXN1, especially the polyQ-expanded form, alleviates disease phenotypes in mice, but the molecular mechanism by which the mutant ATXN1 is specifically modulated is not understood. Here, we identified 22 mutant ATXN1 regulators by performing a cross-species screen of 7787 and 2144 genes in human cells and Drosophila eyes, respectively. Among them, transglutaminase 5 (TG5) preferentially regulated mutant ATXN1 over the WT protein. TG enzymes catalyzed cross-linking of ATXN1 in a polyQ-length–dependent manner, thereby preferentially modulating mutant ATXN1 stability and oligomerization. Perturbing Tg in Drosophila SCA1 models modulated mutant ATXN1 toxicity. Moreover, TG5 was enriched in the nuclei of SCA1-affected neurons and colocalized with nuclear ATXN1 inclusions in brain tissue from patients with SCA1. Our work provides a molecular insight into SCA1 pathogenesis and an opportunity for allele-specific targeting for neurodegenerative disorders.
Authors
Won-Seok Lee, Ismael Al-Ramahi, Hyun-Hwan Jeong, Youjin Jang, Tao Lin, Carolyn J. Adamski, Laura A. Lavery, Smruti Rath, Ronald Richman, Vitaliy V. Bondar, Elizabeth Alcala, Jean-Pierre Revelli, Harry T. Orr, Zhandong Liu, Juan Botas, Huda Y. Zoghbi
Abstract
Mice with experimental nerve damage can display long‑lasting neuropathic pain behavior. We show here that 4 months and later after nerve injury, male but not female mice displayed telomere length (TL) reduction and p53‑mediated cellular senescence in the spinal cord, resulting in maintenance of pain and associated with decreased lifespan. Nerve injury increased the number of p53‑positive spinal cord neurons, astrocytes, and microglia, but only in microglia was the increase male‑specific, matching a robust sex specificity of TL reduction in this cell type, which has been previously implicated in male‑specific pain processing. Pain hypersensitivity was reversed by repeated intrathecal administration of a p53‑specific senolytic peptide, only in male mice and only many months after injury. Analysis of UK Biobank data revealed sex-specific relevance of this pathway in humans, featuring male‑specific genetic association of the human p53 locus (TP53) with chronic pain and a male-specific effect of chronic pain on mortality. Our findings demonstrate the existence of a biological mechanism maintaining pain behavior, at least in males, occurring much later than the time span of virtually all extant preclinical studies.
Authors
Arjun Muralidharan, Susana G. Sotocinal, Noosha Yousefpour, Nur Akkurt, Lucas V. Lima, Shannon Tansley, Marc Parisien, Chengyang Wang, Jean-Sebastien Austin, Boram Ham, Gabrielle M.G.S. Dutra, Philippe Rousseau, Sioui Maldonado-Bouchard, Teleri Clark, Sarah F. Rosen, Mariam R. Majeed, Olivia Silva, Rachel Nejade, Xinyu Li, Stephania Donayre Pimentel, Christopher S. Nielsen, G. Gregory Neely, Chantal Autexier, Luda Diatchenko, Alfredo Ribeiro-da-Silva, Jeffrey S. Mogil
Abstract
Mushroom spine loss and calcium dyshomeostasis are early hallmark events of age-related neurodegeneration, such as Alzheimer’s disease (AD), that are connected with neuronal hyperactivity in early pathology of cognitive brain areas. However, it remains elusive how these key events are triggered at the molecular level for the neuronal abnormality that occurs at the initial stage of disease. Here, we identify downregulated miR-339-5p and its upregulated target protein, neuronatin (Nnat), in cortex neurons from the presenilin-1 M146V knockin (PSEN1-M146V KI) mouse model of familial AD (FAD). Inhibition of miR-339-5p or overexpression of Nnat recapitulates spine loss and endoplasmic reticulum calcium overload in cortical neurons with the PSEN1 mutation. Conversely, either overexpression of miR-339-5p or knockdown of Nnat restores spine morphogenesis and calcium homeostasis. We used fiber photometry recording during the object-cognitive process to further demonstrate that the PSEN1 mutant causes defective habituation in neuronal reaction in the retrosplenial cortex and that this can be rescued by restoring the miR-339-5p/Nnat pathway. Our findings thus reveal crucial roles of the miR-339-5p/Nnat pathway in FAD that may serve as potential diagnostic and therapeutic targets for early pathogenesis.
Authors
Hao-Yu Zou, Lin Guo, Bei Zhang, Si Chen, Xin-Rong Wu, Xian-Dong Liu, Xin-Yu Xu, Bin-Yin Li, Shengdi Chen, Nan-Jie Xu, Suya Sun
Abstract
Food addiction is characterized by a loss of behavioral control over food intake and is associated with obesity and other eating disorders. The mechanisms underlying this behavioral disorder are largely unknown. We aim to investigate the changes in miRNAs expression promoted by food addiction in animals and humans and their involvement in the mechanisms underlying the behavioral hallmarks of this disorder. Sharp similitudes were found between the miRNAs signatures in the medial prefrontal cortex (mPFC) of our animal cohort and the miRNAs circulating levels in our human cohort allowing to identify several miRNAs of potential interest for the development of this disorder. TuD inhibition of miRNA-29c-3p in the mouse mPFC promotes persistence to response and enhances the vulnerability to develop food addiction, whereas miRNA-665-3p inhibition promotes compulsive-like behavior and also enhances food addiction vulnerability. In contrast, miRNA-137-3p inhibition in the mPFC does not affect the development of food addiction. Therefore, miRNA-29c-3p and miRNA-665-3p could be acting as protective factors towards food addiction. The elucidation of these novel epigenetic mechanisms provides advances toward innovative biomarkers and possible future interventions for food addiction and related disorders based on the strategies now available to modify miRNA activity and expression.
Authors
Alejandra García-Blanco, Laura Domingo-Rodriguez, Judit Cabana-Domínguez, Noèlia Fernàndez-Castillo, Laura Pineda-Cirera, Jordi Mayneris-Perxachs, Aurelijus Burokas, Jose Espinosa-Carrasco, Silvia Arboleya, Jessica Latorre, Catherine Stanton, Bru Cormand, Jose-Manuel Fernández-Real, Elena Martín-García, Rafael Maldonado
Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)