A major dose-limiting side effect associated with cancer-treating antineoplastic drugs is the development of neuropathic pain, which is not readily relieved by available analgesics. A better understanding of the mechanisms that underlie pain generation has potential to provide targets for prophylactic management of chemotherapy pain. Here, we delineate a pathway for pain that is induced by the chemotherapeutic drug vincristine sulfate (VCR). In a murine model of chemotherapy-induced allodynia, VCR treatment induced upregulation of endothelial cell adhesion properties, resulting in the infiltration of circulating CX3CR1+ monocytes into the sciatic nerve. At the endothelial-nerve interface, CX3CR1+ monocytes were activated by the chemokine CX3CL1 (also known as fractalkine [FKN]), which promoted production of reactive oxygen species that in turn activated the receptor TRPA1 in sensory neurons and evoked the pain response. Furthermore, mice lacking CX3CR1 exhibited a delay in the development of allodynia following VCR administration. Together, our data suggest that CX3CR1 antagonists and inhibition of FKN proteolytic shedding, possibly by targeting ADAM10/17 and/or cathepsin S, have potential as peripheral approaches for the prophylactic treatment of chemotherapy-induced pain.
Elizabeth A. Old, Suchita Nadkarni, John Grist, Clive Gentry, Stuart Bevan, Ki-Wook Kim, Adrian J. Mogg, Mauro Perretti, Marzia Malcangio
Allan-Herndon-Dudley syndrome (AHDS), a severe form of psychomotor retardation with abnormal thyroid hormone (TH) parameters, is linked to mutations in the TH-specific monocarboxylate transporter MCT8. In mice, deletion of
Steffen Mayerl, Julia Müller, Reinhard Bauer, Sarah Richert, Celia M. Kassmann, Veerle M. Darras, Katrin Buder, Anita Boelen, Theo J. Visser, Heike Heuer
The recent identification of multiple dominant mutations in the gene encoding β-catenin in both humans and mice has enabled exploration of the molecular and cellular basis of β-catenin function in cognitive impairment. In humans, β-catenin mutations that cause a spectrum of neurodevelopmental disorders have been identified. We identified de novo β-catenin mutations in patients with intellectual disability, carefully characterized their phenotypes, and were able to define a recognizable intellectual disability syndrome. In parallel, characterization of a chemically mutagenized mouse line that displays features similar to those of human patients with β-catenin mutations enabled us to investigate the consequences of β-catenin dysfunction through development and into adulthood. The mouse mutant, designated batface (
Valter Tucci, Tjitske Kleefstra, Andrea Hardy, Ines Heise, Silvia Maggi, Marjolein H. Willemsen, Helen Hilton, Chris Esapa, Michelle Simon, Maria-Teresa Buenavista, Liam J. McGuffin, Lucie Vizor, Luca Dodero, Sotirios Tsaftaris, Rosario Romero, Willy N. Nillesen, Lisenka E.L.M. Vissers, Marlies J. Kempers, Anneke T. Vulto-van Silfhout, Zafar Iqbal, Marta Orlando, Alessandro Maccione, Glenda Lassi, Pasqualina Farisello, Andrea Contestabile, Federico Tinarelli, Thierry Nieus, Andrea Raimondi, Barbara Greco, Daniela Cantatore, Laura Gasparini, Luca Berdondini, Angelo Bifone, Alessandro Gozzi, Sara Wells, Patrick M. Nolan
The olfactory bulb (OB) receives odor information from the olfactory epithelium and relays this to the olfactory cortex. Using a mouse model, we found that development and maturation of OB interneurons depends on the zinc finger homeodomain factor teashirt zinc finger family member 1 (TSHZ1). In mice lacking TSHZ1, neuroblasts exhibited a normal tangential migration to the OB; however, upon arrival to the OB, the neuroblasts were distributed aberrantly within the radial dimension, and many immature neuroblasts failed to exit the rostral migratory stream. Conditional deletion of Tshz1 in mice resulted in OB hypoplasia and severe olfactory deficits. We therefore investigated olfaction in human subjects from families with congenital aural atresia that were heterozygous for TSHZ1 loss-of-function mutations. These individuals displayed hyposmia, which is characterized by impaired odor discrimination and reduced olfactory sensitivity. Microarray analysis, in situ hybridization, and ChIP revealed that TSHZ1 bound to and regulated expression of the gene encoding prokineticin receptor 2 (PROKR2), a G protein–coupled receptor essential for OB development. Mutations in PROKR2 lead to Kallmann syndrome, characterized by anosmia and hypogonadotrophic hypogonadism. Our data indicate that TSHZ1 is a key regulator of mammalian OB development and function and controls the expression of molecules involved in human Kallmann syndrome.
Daniela Ragancokova, Elena Rocca, Anne M.M. Oonk, Herbert Schulz, Elvira Rohde, Jan Bednarsch, Ilse Feenstra, Ronald J.E. Pennings, Hagen Wende, Alistair N. Garratt
The autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) results from low levels of survival motor neuron (SMN) protein; however, it is unclear how reduced SMN promotes SMA development. Here, we determined that ubiquitin-dependent pathways regulate neuromuscular pathology in SMA. Using mouse models of SMA, we observed widespread perturbations in ubiquitin homeostasis, including reduced levels of ubiquitin-like modifier activating enzyme 1 (UBA1). SMN physically interacted with UBA1 in neurons, and disruption of
Thomas M. Wishart, Chantal A. Mutsaers, Markus Riessland, Michell M. Reimer, Gillian Hunter, Marie L. Hannam, Samantha L. Eaton, Heidi R. Fuller, Sarah L. Roche, Eilidh Somers, Robert Morse, Philip J. Young, Douglas J. Lamont, Matthias Hammerschmidt, Anagha Joshi, Peter Hohenstein, Glenn E. Morris, Simon H. Parson, Paul A. Skehel, Thomas Becker, Iain M. Robinson, Catherina G. Becker, Brunhilde Wirth, Thomas H. Gillingwater
Familial Alzheimer’s disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred carrying the PS1-E280A mutation is the largest known cohort of PS1-FAD patients. Here, we investigated PS1-E280A–associated cerebellar dysfunction and found that it occurs early in PS1-E208A carriers, while cerebellar signs are highly prevalent in patients with dementia. Postmortem analysis of cerebella of PS1-E280A carrier revealed greater Purkinje cell (PC) loss and more abnormal mitochondria compared with controls. In PS1-E280A tissue, ER/mitochondria tethering was impaired, Ca2+ channels IP3Rs and CACNA1A were downregulated, and Ca2+-dependent mitochondrial transport proteins MIRO1 and KIF5C were reduced. Accordingly, expression of PS1-E280A in a neuronal cell line altered ER/mitochondria tethering and transport compared with that in cells expressing wild-type PS1. In a murine model of PS1-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar β-amyloid deposition. Our data suggest that impaired calcium homeostasis and mitochondrial dysfunction in PS1-FAD PCs reduces their activity and contributes to motor coordination deficits prior to Aβ aggregation and dementia. We propose that PS1-E280A affects both Ca2+ homeostasis and Aβ precursor processing, leading to FAD and neurodegeneration.
Diego Sepulveda-Falla, Alvaro Barrera-Ocampo, Christian Hagel, Anne Korwitz, Maria Fernanda Vinueza-Veloz, Kuikui Zhou, Martijn Schonewille, Haibo Zhou, Luis Velazquez-Perez, Roberto Rodriguez-Labrada, Andres Villegas, Isidro Ferrer, Francisco Lopera, Thomas Langer, Chris I. De Zeeuw, Markus Glatzel
Increasing evidence indicates that the pathogenesis of neuropathic pain is mediated through spinal cord microglia activation. The intracellular protease caspase-6 (CASP6) is known to regulate neuronal apoptosis and axonal degeneration; however, the contribution of microglia and CASP6 in modulating synaptic transmission and pain is unclear. Here, we found that CASP6 is expressed specifically in C-fiber axonal terminals in the superficial spinal cord dorsal horn. Animals exposed to intraplantar formalin or bradykinin injection exhibited CASP6 activation in the dorsal horn.
Temugin Berta, Chul-Kyu Park, Zhen-Zhong Xu, Ruo-Gang Xie, Tong Liu, Ning Lü, Yen-Chin Liu, Ru-Rong Ji
Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson’s disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11C-DASB PET to evaluate serotonin terminal function and 11C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD.
Marios Politis, Kit Wu, Clare Loane, David J. Brooks, Lorenzo Kiferle, Federico E. Turkheimer, Peter Bain, Sophie Molloy, Paola Piccini
Neurotensin (NT) has emerged as an important modulator of nociceptive transmission and exerts its biological effects through interactions with 2 distinct GPCRs, NTS1 and NTS2. NT provides strong analgesia when administered directly into the brain; however, the blood-brain barrier (BBB) is a major obstacle for effective delivery of potential analgesics to the brain. To overcome this challenge, we synthesized chemical conjugates that are transported across the BBB via receptor-mediated transcytosis using the brain-penetrant peptide Angiopep-2 (An2), which targets LDL receptor–related protein-1 (LRP1). Using in situ brain perfusion in mice, we found that the compound ANG2002, a conjugate of An2 and NT, was transported at least 10 times more efficiently across the BBB than native NT. In vitro, ANG2002 bound NTS1 and NTS2 receptors and maintained NT-associated biological activity. In rats, i.v. ANG2002 induced a dose-dependent analgesia in the formalin model of persistent pain. At a dose of 0.05 mg/kg, ANG2002 effectively reversed pain behaviors induced by the development of neuropathic and bone cancer pain in animal models. The analgesic properties of ANG2002 demonstrated in this study suggest that this compound is effective for clinical management of persistent and chronic pain and establish the benefits of this technology for the development of neurotherapeutics.
Michel Demeule, Nicolas Beaudet, Anthony Régina, Élie Besserer-Offroy, Alexandre Murza, Pascal Tétreault, Karine Belleville, Christian Ché, Alain Larocque, Carine Thiot, Richard Béliveau, Jean-Michel Longpré, Éric Marsault, Richard Leduc, Jean E. Lachowicz, Steven L. Gonias, Jean-Paul Castaigne, Philippe Sarret
Autosomal dominant mutations of the RNA/DNA binding protein FUS are linked to familial amyotrophic lateral sclerosis (FALS); however, it is not clear how FUS mutations cause neurodegeneration. Using transgenic mice expressing a common FALS-associated FUS mutation (FUS-R521C mice), we found that mutant FUS proteins formed a stable complex with WT FUS proteins and interfered with the normal interactions between FUS and histone deacetylase 1 (HDAC1). Consequently, FUS-R521C mice exhibited evidence of DNA damage as well as profound dendritic and synaptic phenotypes in brain and spinal cord. To provide insights into these defects, we screened neural genes for nucleotide oxidation and identified brain-derived neurotrophic factor (
Haiyan Qiu, Sebum Lee, Yulei Shang, Wen-Yuan Wang, Kin Fai Au, Sherry Kamiya, Sami J. Barmada, Steven Finkbeiner, Hansen Lui, Caitlin E. Carlton, Amy A. Tang, Michael C. Oldham, Hejia Wang, James Shorter, Anthony J. Filiano, Erik D. Roberson, Warren G. Tourtellotte, Bin Chen, Li-Huei Tsai, Eric J. Huang