Lancl1 Promotes Motor Neuron Survival and Extends the Lifespan of Amyotrophic Lateral Sclerosis Mice
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Exosome TDP-43 Profile in Canine Model of ALS: a Preliminary Study in Developing Surrogate Biomarker
bioRxiv preprint doi: https://doi.org/10.1101/2021.06.17.448876; this version posted June 18, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Exosome TDP-43 profile in canine model of ALS: A preliminary study in developing surrogate biomarker Penelope Pfeiffer 1, Joan R. Coates 2, Andrew Kennedy3, Kyleigh Getchell3, Edina Kosa3, Abdulbaki Agbas 3, 4* 1 Mount Sinai Hospital, Chicago IL; [email protected] 2 University of Missouri-Columbia, MO; [email protected] 3 Kansas City University, Kansas City MO; [email protected]; [email protected]; [email protected]; [email protected] 4 Heartland Center for Mitochondrial Medicine, Kansas City KS * Correspondence: [email protected]; Tel.: +1 816-654-7614 Abstract: Blood-based biomarkers are much-needed diagnostic and prognostic tools for ALS. Canine degenerative myelopathy (DM) is recognized animal disease model to study the biology of human ALS. Serum derived exosomes are potential carrier that transport intercellular hormone-like messengers, together with their stability as carrier of proteins and RNA, make them ideal as biomarkers for a variety of diseases and biological processes. We study exosomal TDP-43 pattern as a surrogate biomarker that reflects biochemical changes in central nervous system. We isolated exosomes from canine serum using commercial exosome isolation reagents. TDP-43 and SOD1 profile in spinal cord homogenate lysate and that of serum-derived exosomes were found elevated in dogs with DM. -
Neural Control of Movement: Motor Neuron Subtypes, Proprioception and Recurrent Inhibition
List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Enjin A, Rabe N, Nakanishi ST, Vallstedt A, Gezelius H, Mem- ic F, Lind M, Hjalt T, Tourtellotte WG, Bruder C, Eichele G, Whelan PJ, Kullander K (2010) Identification of novel spinal cholinergic genetic subtypes disclose Chodl and Pitx2 as mark- ers for fast motor neurons and partition cells. J Comp Neurol 518:2284-2304. II Wootz H, Enjin A, Wallen-Mackenzie Å, Lindholm D, Kul- lander K (2010) Reduced VGLUT2 expression increases motor neuron viability in Sod1G93A mice. Neurobiol Dis 37:58-66 III Enjin A, Leao KE, Mikulovic S, Le Merre P, Tourtellotte WG, Kullander K. 5-ht1d marks gamma motor neurons and regulates development of sensorimotor connections Manuscript IV Enjin A, Leao KE, Eriksson A, Larhammar M, Gezelius H, Lamotte d’Incamps B, Nagaraja C, Kullander K. Development of spinal motor circuits in the absence of VIAAT-mediated Renshaw cell signaling Manuscript Reprints were made with permission from the respective publishers. Cover illustration Carousel by Sasha Svensson Contents Introduction.....................................................................................................9 Background...................................................................................................11 Neural control of movement.....................................................................11 The motor neuron.....................................................................................12 Organization -
ALS and Other Motor Neuron Diseases Can Represent Diagnostic Challenges
Review Article Address correspondence to Dr Ezgi Tiryaki, Hennepin ALS and Other Motor County Medical Center, Department of Neurology, 701 Park Avenue P5-200, Neuron Diseases Minneapolis, MN 55415, [email protected]. Ezgi Tiryaki, MD; Holli A. Horak, MD, FAAN Relationship Disclosure: Dr Tiryaki’s institution receives support from The ALS Association. Dr Horak’s ABSTRACT institution receives a grant from the Centers for Disease Purpose of Review: This review describes the most common motor neuron disease, Control and Prevention. ALS. It discusses the diagnosis and evaluation of ALS and the current understanding of its Unlabeled Use of pathophysiology, including new genetic underpinnings of the disease. This article also Products/Investigational covers other motor neuron diseases, reviews how to distinguish them from ALS, and Use Disclosure: Drs Tiryaki and Horak discuss discusses their pathophysiology. the unlabeled use of various Recent Findings: In this article, the spectrum of cognitive involvement in ALS, new concepts drugs for the symptomatic about protein synthesis pathology in the etiology of ALS, and new genetic associations will be management of ALS. * 2014, American Academy covered. This concept has changed over the past 3 to 4 years with the discovery of new of Neurology. genes and genetic processes that may trigger the disease. As of 2014, two-thirds of familial ALS and 10% of sporadic ALS can be explained by genetics. TAR DNA binding protein 43 kDa (TDP-43), for instance, has been shown to cause frontotemporal dementia as well as some cases of familial ALS, and is associated with frontotemporal dysfunction in ALS. Summary: The anterior horn cells control all voluntary movement: motor activity, res- piratory, speech, and swallowing functions are dependent upon signals from the anterior horn cells. -
The Good and the Bad of CRISPR/Cas9 Genome Editing
Replicating human disease in rodents: the good and the bad of CRISPR/Cas9 genome editing Guillaume Pavlovic, PhD Head of Unit at PHENOMIN ‐ Institut Clinique de la Souris email: [email protected] CMC Strategy Forum Europe linkedIn: http://bit.ly/2VMLoJ9 Understanding Human disease with rodents: three challenges phenotypes of protein Some failure of mice and other coding genes in Mouse model organisms studies to be replicated or translated to humans Multiple phenotypes No known Knowledge Translation phenotype on disease from rodent One genes to Human phenotype Probability of success Reproducibility of preclinical studies https://www.mousephenotype.org/ 50% of preclinical data are irreproducible CRISPR/Cas9 genome editing in rodents THE GOOD What new possibilities does CRISPR open to better mimic human diseases ? – The genetic context (background) is not adapted – The designed mutation does not mimic the Human pathology With CRISPR/Cas9 new types of mutations can be easily engineered THE BAD There is more than off targets ! Understanding CRISPR/Cas9 genome editing to reduce lack of reproducibility – You are facing experimental variability, poor experimental design or bad reproducibility why do the results discovered using in vivo models sometimes fail to translate to human disease? Plenty of literature showing that the inbred genetic background has an effect on the phenotype Cerebellar phenotype of En1Hd/Hd mutants on 129/Sv and C57BL/6J backgrounds. deletion of the cerebellum 129/Sv—En1Hd/Hd C57BL/6J—En1Hd/Hd Bilovocky et al. J. Neurosci. 2003 why do the results discovered using in vivo models sometimes fail to translate to human disease? Plenty of literature showing that the inbred genetic background has an effect on the phenotype genetic background limits generalizability of genotype-phenotype relationships Sittig et al. -
Current and Emerging Treatment Options for Endometriosis
Expert Opinion on Pharmacotherapy ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20 Current and emerging treatment options for endometriosis Simone Ferrero, Giulio Evangelisti & Fabio Barra To cite this article: Simone Ferrero, Giulio Evangelisti & Fabio Barra (2018): Current and emerging treatment options for endometriosis, Expert Opinion on Pharmacotherapy, DOI: 10.1080/14656566.2018.1494154 To link to this article: https://doi.org/10.1080/14656566.2018.1494154 Published online: 05 Jul 2018. Submit your article to this journal View Crossmark data Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ieop20 EXPERT OPINION ON PHARMACOTHERAPY https://doi.org/10.1080/14656566.2018.1494154 REVIEW Current and emerging treatment options for endometriosis Simone Ferrero a,b, Giulio Evangelistia,b and Fabio Barra a,b aAcademic Unit of Obstetrics and Gynecology, Ospedale Policlinico San Martino, Genoa, Italy; bDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy ABSTRACT ARTICLE HISTORY Introduction: Pharmacotherapy has a pivotal role in the management of endometriosis with long-term Received 8 June 2018 treatments balancing clinical efficacy (control of pain symptoms and prevention of recurrence of the Accepted 25 June 2018 disease after surgery) with an acceptable safety profile. Treatment choice is based on several factors KEYWORDS including age and patient preference, reproductive plans, intensity of pain, severity of disease and Endometriosis; combined incidence of adverse effects. oral contraceptives; Areas covered: The aim of this review is to provide the reader with a complete overview of drugs that progestins; gonadotropin- are currently available or are under investigation for the treatment of endometriosis highlighting on- releasing hormone agonist; going clinical trials. -
Preliminary Evidence for an Influence of Exposure to Polycyclic Aromatic
Zhang et al. BMC Pediatrics (2021) 21:86 https://doi.org/10.1186/s12887-021-02539-w RESEARCH ARTICLE Open Access Preliminary evidence for an influence of exposure to polycyclic aromatic hydrocarbons on the composition of the gut microbiota and neurodevelopment in three-year-old healthy children Wei Zhang1†, Zhongqing Sun2†,QianZhang3†,ZhitaoSun4,YaSu4,JiahuiSong1,BinglingWang4* and Ruqin Gao4* Abstract Background: During the second and third year after birth the gut microbiota (GM) is subjected to important development. The polycyclic aromatic hydrocarbon (PAH) exposure could influence the GM in animal and early postnatal exposure is associated with neurodevelopment disorder in children. This study was designed to explore the possible influence of the polycyclic aromatic hydrocarbons (PAHs) on the composition of the gut microbiota (GM) and neurodevelopment in a sample of 38 healthy children at the age of 3 years. Methods: A brief development (Gesell Development Inventory, GDI) and behavior test (Child Behavior Checklist, CBCL) were completed on 3-yr-olds and stool samples were collected for 16S rRNA V4-V5 sequencing. The PAH- DNA adduct in the umbilical cord blood and the urinary hydroxyl PAHs (OH-PAHs) at the age of 12 months were measured as pre- and postnatal PAH exposure, respectively. Results: The most abundant two phyla were Bacteroidetes (68.6%) and Firmicutes (24.2%). The phyla Firmicutes, Actinobacteria, Proteobacteria, Tenericutes, and Lentisphaerae were positively correlated with most domain behaviors of the GDI, whereas the Bacteroidetes, Cyanobacteria, and Fusobacteria were negatively correlated. Correspondingly, the phyla Bacteroidetes, Actinobacteria, and Fusobacteria showed positive correlations with most CBCL core and broadband syndromes, whereas the Firmicutes, Verrucomicrobia, Synergistetes, Proteobacteria and Tenericules were negatively correlated. -
The Myelin-Forming Cells of the Nervous System (Oligodendrocytes and Schwann Cells)
The Myelin-Forming Cells of the Nervous System (oligodendrocytes and Schwann cells) Oligodendrocyte Schwann Cell Oligodendrocyte function Saltatory (jumping) nerve conduction Oligodendroglia PMD PMD Saltatory (jumping) nerve conduction Investigating the Myelinogenic Potential of Individual Oligodendrocytes In Vivo Sparse Labeling of Oligodendrocytes CNPase-GFP Variegated expression under the MBP-enhancer Cerebral Cortex Corpus Callosum Cerebral Cortex Corpus Callosum Cerebral Cortex Caudate Putamen Corpus Callosum Cerebral Cortex Caudate Putamen Corpus Callosum Corpus Callosum Cerebral Cortex Caudate Putamen Corpus Callosum Ant Commissure Corpus Callosum Cerebral Cortex Caudate Putamen Piriform Cortex Corpus Callosum Ant Commissure Characterization of Oligodendrocyte Morphology Cerebral Cortex Corpus Callosum Caudate Putamen Cerebellum Brain Stem Spinal Cord Oligodendrocytes in disease: Cerebral Palsy ! CP major cause of chronic neurological morbidity and mortality in children ! CP incidence now about 3/1000 live births compared to 1/1000 in 1980 when we started intervening for ELBW ! Of all ELBW {gestation 6 mo, Wt. 0.5kg} , 10-15% develop CP ! Prematurely born children prone to white matter injury {WMI}, principle reason for the increase in incidence of CP ! ! 12 Cerebral Palsy Spectrum of white matter injury ! ! Macro Cystic Micro Cystic Gliotic Khwaja and Volpe 2009 13 Rationale for Repair/Remyelination in Multiple Sclerosis Oligodendrocyte specification oligodendrocytes specified from the pMN after MNs - a ventral source of oligodendrocytes -
Cortex Brainstem Spinal Cord Thalamus Cerebellum Basal Ganglia
Harvard-MIT Division of Health Sciences and Technology HST.131: Introduction to Neuroscience Course Director: Dr. David Corey Motor Systems I 1 Emad Eskandar, MD Motor Systems I - Muscles & Spinal Cord Introduction Normal motor function requires the coordination of multiple inter-elated areas of the CNS. Understanding the contributions of these areas to generating movements and the disturbances that arise from their pathology are important challenges for the clinician and the scientist. Despite the importance of diseases that cause disorders of movement, the precise function of many of these areas is not completely clear. The main constituents of the motor system are the cortex, basal ganglia, cerebellum, brainstem, and spinal cord. Cortex Basal Ganglia Cerebellum Thalamus Brainstem Spinal Cord In very broad terms, cortical motor areas initiate voluntary movements. The cortex projects to the spinal cord directly, through the corticospinal tract - also known as the pyramidal tract, or indirectly through relay areas in the brain stem. The cortical output is modified by two parallel but separate re entrant side loops. One loop involves the basal ganglia while the other loop involves the cerebellum. The final outputs for the entire system are the alpha motor neurons of the spinal cord, also called the Lower Motor Neurons. Cortex: Planning and initiation of voluntary movements and integration of inputs from other brain areas. Basal Ganglia: Enforcement of desired movements and suppression of undesired movements. Cerebellum: Timing and precision of fine movements, adjusting ongoing movements, motor learning of skilled tasks Brain Stem: Control of balance and posture, coordination of head, neck and eye movements, motor outflow of cranial nerves Spinal Cord: Spontaneous reflexes, rhythmic movements, motor outflow to body. -
Motor Neuron Disease Motor Neuron Disease
Motor Neuron Disease Motor Neuron Disease • Incidence: 2-4 per 100 000 • Onset: usually 50-70 years • Pathology: – Degenerative condition – anterior horn cells and upper motor neurons in spinal cord, resulting in mixed upper and lower motor neuron signs • Cause unknown – 10% familial (SOD-1 mutation) – ? Related to athleticism Presentation • Several variations in onset, but progress to the same endpoint • Motor nerves only affected • May be just UMN or just LMN at onset, but other features will appear over time • Main patterns: – Amyotrophic lateral sclerosis – Bulbar presentaion – Primary lateral sclerosis (UMN onset) – Progressive muscular atrophy (LMN onset) Questions Wasting Classification • Amyotrophic Lateral Sclerosis • Progressive Bulbar Palsy • Progressive Muscular Atrophy • Primary Lateral Sclerosis • Multifocal Motor Neuropathy • Spinal Muscular Atrophy • Kennedy’s Disease • Monomelic Amyotrophy • Brachial Amyotrophic Diplegia El Escorial Criteria for Diagnosis Tongue fasiculations Amyotrophic lateral sclerosis • ‘Typical’ presentation (60%+) • Usually one limb initially – Foot drop – Clumsy weak hand – May complain of cramps • Gradual progression over months • May be some wasting at presentation • Usually fasiculations (often more widespread) • Brisk reflexes, extensor plantars • No sensory signs; MAY occasionally be mild symptoms • Relentless progression, noticable over weeks/ months Bulbar MND • Approximately 30% of cases • Onset with dysarthria, dysphagia • Bulbar and pseudobulbar symptoms • On examination – Dysarthria – -
Olig2 Precursors Produce Abducens Motor Neurons and Oligodendrocytes in the Zebrafish Hindbrain
2322 • The Journal of Neuroscience, February 25, 2009 • 29(8):2322–2333 Cellular/Molecular Olig2ϩ Precursors Produce Abducens Motor Neurons and Oligodendrocytes in the Zebrafish Hindbrain Denise A. Zannino1,2 and Bruce Appel1,3 1Program in Neuroscience and 2Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37235, and 3Department of Pediatrics, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado 80045 During development, a specific subset of ventral spinal cord precursors called pMN cells produces first motor neurons and then oligo- dendrocyte progenitor cells (OPCs), which migrate, divide and differentiate as myelinating oligodendrocytes. pMN cells express the Olig2 transcription factor and Olig2 function is necessary for formation of spinal motor neurons and OPCs. In the hindbrain and midbrain, distinct classes of visceral, branchiomotor and somatic motor neurons are organized as discrete nuclei, and OPCs are broadly distributed. Mouse embryos deficient for Olig2 function lack somatic motor neurons and OPCs, but it is not clear whether this reflects a common origin for these cells, similar to spinal cord, or independent requirements for Olig2 function in somatic motor neuron and OPC develop- ment. We investigated cranial motor neuron and OPC development in zebrafish and found, using a combination of transgenic reporters and cell type specific antibodies, that somatic abducens motor neurons and a small subset of OPCs arise from common olig2ϩ neuroep- ithelial precursors in rhombomeres r5 and r6, but that all other motor neurons and OPCs do not similarly develop from shared pools of olig2ϩ precursors. In the absence of olig2 function, r5 and r6 precursors remain in the cell cycle and fail to produce abducens motor neurons, and OPCs are entirely lacking in the hindbrain. -
Gamma Motor Neurons Survive and Exacerbate Alpha Motor Neuron Degeneration In
Gamma motor neurons survive and exacerbate alpha PNAS PLUS motor neuron degeneration in ALS Melanie Lalancette-Heberta,b, Aarti Sharmaa,b, Alexander K. Lyashchenkoa,b, and Neil A. Shneidera,b,1 aCenter for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032; and bDepartment of Neurology, Columbia University, New York, NY 10032 Edited by Rob Brownstone, University College London, London, United Kingdom, and accepted by Editorial Board Member Fred H. Gage October 27, 2016 (received for review April 4, 2016) The molecular and cellular basis of selective motor neuron (MN) the muscle spindle and control the sensitivity of spindle afferent vulnerability in amyotrophic lateral sclerosis (ALS) is not known. In discharge (15); beta (β) skeletofusimotor neurons innervate both genetically distinct mouse models of familial ALS expressing intra- and extrafusal muscle (16). In addition to morphological mutant superoxide dismutase-1 (SOD1), TAR DNA-binding protein differences, distinct muscle targets, and the absence of primary 43 (TDP-43), and fused in sarcoma (FUS), we demonstrate selective afferent (IA)inputsonγ-MNs, these functional MN subtypes also degeneration of alpha MNs (α-MNs) and complete sparing of differ in their trophic requirements, and γ-MNs express high levels gamma MNs (γ-MNs), which selectively innervate muscle spindles. of the glial cell line-derived neurotropic factor (GDNF) receptor Resistant γ-MNs are distinct from vulnerable α-MNs in that they Gfrα1 (17). γ-MNs are also molecularly distinguished by the ex- lack synaptic contacts from primary afferent (IA) fibers. Elimination pression of other selective markers including the transcription α of these synapses protects -MNs in the SOD1 mutant, implicating factor Err3 (18), Wnt7A (19), the serotonin receptor 1d (5-ht1d) this excitatory input in MN degeneration. -
Olig2 Is Required for Zebrafish Primary Motor Neuron and Oligodendrocyte Development
Developmental Biology 248, 356–368 (2002) doi:10.1006/dbio.2002.0738 olig2 Is Required for Zebrafish Primary Motor Neuron and Oligodendrocyte Development Hae-Chul Park, Amit Mehta, Joanna S. Richardson, and Bruce Appel1 Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37235 Oligodendrocytes are produced from the same region of the ventral spinal cord that earlier generated motor neurons in bird and rodent embryos. Motor neuron and oligodendrocyte precursor cells express Olig genes, which encode basic helix–loop– helix transcription factors that play important roles in the development of both motor neurons and oligodendrocytes. We found that oligodendrocytes develop similarly in zebrafish embryos, in that they arise from ventral spinal cord and migrate to new positions. Developing primary motor neurons and oligodendrocytes express olig2 as do neural plate cells that give rise to both primary motor neurons and oligodendrocytes. Loss of olig2 function prevented primary motor neuron and oligodendrocyte development, whereas olig2 overexpression promoted formation of excess primary motor neurons and oligodendrocytes. We provide genetic evidence that Hedgehog signaling is required for zebrafish olig2 expression and oligodendrocyte development. However, olig2 overexpression did not promote primary motor neuron or oligodendrocyte development in embryos with reduced Hedgehog signaling activity. One possibility consistent with these data is that Hedgehog signaling, partly by inducing olig2 expression, specifies neural precursor cells that have potential for primary motor neuron or oligodendrocyte fate. © 2002 Elsevier Science (USA) Key Words: zebrafish; oligodendrocyte; glia; motor neuron; spinal cord; neurogenesis; Hedgehog; Olig. INTRODUCTION encode basic helix–loop–helix (bHLH) transcription factors, are important for motor neuron and oligodendrocyte devel- During vertebrate development, multipotent neural pre- opment.