A transgenic mouse expressing CHMP2Bintron5 mutant in neurons develops histological and behavioural features of amyotrophic lateral sclerosis and frontotemporal dementia.

Mutations in the charged multivesicular body protein 2B (CHMP2B) are associated with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and with a mixed ALS-FTD syndrome. To model this syndrome, we generated a transgenic mouse line expressing the human CHMP2Bintron5 mutant in a neuron-specific manner. These mice developed a dose-dependent disease phenotype. A longitudinal study revealed progressive gait abnormalities, reduced muscle strength and decreased motor coordination. CHMP2Bintron5 mice died due to generalized paralysis. When paralyzed, signs of denervation were present as attested by altered electromyographic profiles, by decreased number of fully innervated neuromuscular junctions, by reduction in size of motor endplates and by a decrease of sciatic nerve axons area. However, spinal motor neurons cell bodies were preserved until death. In addition to the motor dysfunctions, CHMP2Bintron5 mice progressively developed FTD-relevant behavioural modifications such as disinhibition, stereotypies, decrease in social interactions, compulsivity and change in dietary preferences. Furthermore, neurons in the affected spinal cord and brain regions showed accumulation of p62-positive cytoplasmic inclusions associated or not with ubiquitin and CHMP2Bintron5 As observed in FTD3 patients, these inclusions were negative for TDP-43 and FUS. Moreover, astrogliosis and microgliosis developed with age. Altogether, these data indicate that the neuronal expression of human CHMP2Bintron5 in areas involved in motor and cognitive functions induces progressive motor alterations associated with dementia symptoms and with histopathological hallmarks reminiscent of both ALS and FTD.

[1]  J. Silver,et al.  Regulation of Thy-1 gene expression in transgenic mice , 1987, Cell.

[2]  A. Pramatarova,et al.  Neuron-Specific Expression of Mutant Superoxide Dismutase 1 in Transgenic Mice Does Not Lead to Motor Impairment , 2001, The Journal of Neuroscience.

[3]  J. Hodges,et al.  Motor neurone disease, dementia and aphasia: coincidence, co-occurrence or continuum? , 2001, Journal of Neurology.

[4]  P. Johannsen,et al.  A Reassessment of the Neuropathology of Frontotemporal Dementia Linked to Chromosome 3 , 2007, Journal of neuropathology and experimental neurology.

[5]  T. Hortobágyi,et al.  Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion , 2012, Acta Neuropathologica.

[6]  R. Oppenheim,et al.  Complete Dissociation of Motor Neuron Death from Motor Dysfunction by Bax Deletion in a Mouse Model of ALS , 2006, The Journal of Neuroscience.

[7]  Pico Caroni,et al.  Overexpression of growth-associated proteins in the neurons of adult transgenic mice , 1997, Journal of Neuroscience Methods.

[8]  Victoria Del Gaizo Moore,et al.  Characterization of early pathogenesis in the SOD1G93A mouse model of ALS: part I, background and methods , 2013, Brain and behavior.

[9]  J R Hodges,et al.  The prevalence of frontotemporal dementia , 2002, Neurology.

[10]  J. Glass,et al.  Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man , 2004, Experimental Neurology.

[11]  Erik Sahai,et al.  Deficits in axonal transport precede ALS symptoms in vivo , 2010, Proceedings of the National Academy of Sciences.

[12]  Holger Hummerich,et al.  Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia , 2005, Nature Genetics.

[13]  H. Kawakami,et al.  A unique pattern of astrocytosis in the primary motor area in amyotrophic lateral sclerosis , 1991, Acta Neuropathologica.

[14]  Roland G Henry,et al.  Continuum of frontal lobe impairment in amyotrophic lateral sclerosis. , 2007, Archives of neurology.

[15]  C. Shaw,et al.  Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content. , 2007, Human molecular genetics.

[16]  F. Sellal,et al.  Evaluating Behavior in Mouse Models of the Behavioral Variant of Frontotemporal Dementia: Which Test for Which Symptom? , 2015, Neurodegenerative Diseases.

[17]  J. Collinge,et al.  ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B) , 2006, Neurology.

[18]  Sonja W. Scholz,et al.  Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS , 2010, Neuron.

[19]  Patrick Santens,et al.  CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro. , 2008, Human molecular genetics.

[20]  A. Echaniz-Laguna,et al.  Electrophysiological studies in a mouse model of Schwartz–Jampel syndrome demonstrate muscle fiber hyperactivity of peripheral nerve origin , 2009, Muscle & nerve.

[21]  L. Fagni,et al.  Regulation of Postsynaptic Function by the Dementia-Related ESCRT-III Subunit CHMP2B , 2015, The Journal of Neuroscience.

[22]  P. Caroni,et al.  Accumulation of SOD1 Mutants in Postnatal Motoneurons Does Not Cause Motoneuron Pathology or Motoneuron Disease , 2002, The Journal of Neuroscience.

[23]  P. Johannsen,et al.  Frontotemporal Dementia Caused by CHMP2B Mutations , 2011, Current Alzheimer research.

[24]  R. Eftimie,et al.  Myogenin and MyoD join a family of skeletal muscle genes regulated by electrical activity. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[25]  L. Petrucelli,et al.  Alterations in microRNA-124 and AMPA receptors contribute to social behavioral deficits in frontotemporal dementia , 2014, Nature Medicine.

[26]  A. M. Correia,et al.  Early Changes of Neuromuscular Transmission in the SOD1(G93A) Mice Model of ALS Start Long before Motor Symptoms Onset , 2013, PloS one.

[27]  A. Ludolph,et al.  Energy metabolism in amyotrophic lateral sclerosis , 2011, The Lancet Neurology.

[28]  C. Hoogenraad,et al.  Neuron-Specific Expression of Mutant Superoxide Dismutase Is Sufficient to Induce Amyotrophic Lateral Sclerosis in Transgenic Mice , 2008, The Journal of Neuroscience.

[29]  K. Verbanac,et al.  Real-time PCR to determine transgene copy number and to quantitate the biolocalization of adoptively transferred cells from EGFP-transgenic mice. , 2008, BioTechniques.

[30]  D. Schiffer,et al.  Reactive astrogliosis of the spinal cord in amyotrophic lateral sclerosis , 1996, Journal of the Neurological Sciences.

[31]  Paul G. Ince,et al.  Mutations in CHMP2B in Lower Motor Neuron Predominant Amyotrophic Lateral Sclerosis (ALS) , 2010, PloS one.

[32]  O. Hardiman,et al.  The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study , 2011, Journal of Neurology, Neurosurgery & Psychiatry.

[33]  B. Dubois,et al.  CHMP2B mutations are rare in French families with frontotemporal lobar degeneration , 2010, Journal of Neurology.

[34]  J. Morrison,et al.  Time course of neuropathology in the spinal cord of G86R superoxide dismutase transgenic mice , 1998, The Journal of comparative neurology.

[35]  P. Heutink,et al.  CHMP2B mutations are not a cause of dementia in Dutch patients with familial and sporadic frontotemporal dementia , 2006, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[36]  S Gydesen,et al.  Chromosome 3 linked frontotemporal dementia (FTD-3) , 2002, Neurology.

[37]  B. Miller,et al.  Frontotemporal dementia: a bridge between dementia and neuromuscular disease , 2015, Annals of the New York Academy of Sciences.

[38]  J. Changeux,et al.  Acetylcholine receptor gene expression at the developing neuromuscular junction. , 1995, Physiological reviews.

[39]  N. Cairns,et al.  TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration , 2009, Proceedings of the National Academy of Sciences.

[40]  V. Meininger,et al.  Amyotrophic lateral sclerosis: all roads lead to Rome , 2007, Journal of neurochemistry.

[41]  C. van Broeckhoven,et al.  Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations , 2010, Human molecular genetics.

[42]  S. Young,et al.  ESCRT-III Dysfunction Causes Autophagosome Accumulation and Neurodegeneration , 2007, Current Biology.

[43]  Peter H. L. Krijger,et al.  Targeted sequencing by proximity ligation for comprehensive variant detection and local haplotyping , 2014, Nature Biotechnology.

[44]  A. Ludolph,et al.  Mice with a mutation in the dynein heavy chain 1 gene display sensory neuropathy but lack motor neuron disease , 2009, Experimental Neurology.

[45]  T. Siddique,et al.  What is repeated in ALS and FTLD , 2012, The Lancet Neurology.

[46]  A. Echaniz-Laguna,et al.  Sodium Valproate Exerts Neuroprotective Effects In Vivo through CREB-Binding Protein-Dependent Mechanisms But Does Not Improve Survival in an Amyotrophic Lateral Sclerosis Mouse Model , 2007, The Journal of Neuroscience.

[47]  J. Collinge,et al.  Frontotemporal dementia caused by CHMP2B mutation is characterised by neuronal lysosomal storage pathology , 2015, Acta Neuropathologica.

[48]  E. K. Bjornskov,et al.  Quantitative axon terminal and end-plate morphology in amyotrophic lateral sclerosis. , 1984, Archives of neurology.

[49]  D. Cleveland,et al.  Converging Mechanisms in ALS and FTD: Disrupted RNA and Protein Homeostasis , 2013, Neuron.

[50]  Xun Hu,et al.  TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis , 2008, Science.

[51]  Bruce L. Miller,et al.  Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS , 2011, Neuron.

[52]  A. Lannuzel,et al.  Clinical varieties and epidemiological aspects of amyotrophic lateral sclerosis in the Caribbean island of Guadeloupe: A new focus of ALS associated with Parkinsonism , 2015, Amyotrophic lateral sclerosis & frontotemporal degeneration.

[53]  Valerie J. Bolivar,et al.  A novel social proximity test suggests patterns of social avoidance and gaze aversion-like behavior in BTBR T+ tf/J mice , 2011, Behavioural Brain Research.

[54]  T. Siddique,et al.  Protein recycling pathways in neurodegenerative diseases , 2014, Alzheimer's Research & Therapy.

[55]  I. Mackenzie,et al.  Absence of FUS-immunoreactive pathology in frontotemporal dementia linked to chromosome 3 (FTD-3) caused by mutation in the CHMP2B gene , 2009, Acta Neuropathologica.

[56]  Victoria Del Gaizo Moore,et al.  Characterization of early pathogenesis in the SOD1G93A mouse model of ALS: part II, results and discussion , 2013, Brain and behavior.

[57]  D. Yves von Cramon,et al.  Towards a nosology for frontotemporal lobar degenerations—A meta-analysis involving 267 subjects , 2007, NeuroImage.

[58]  A. Al-Chalabi,et al.  The genetics and neuropathology of amyotrophic lateral sclerosis , 2012, Acta Neuropathologica.

[59]  David Heckerman,et al.  A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD , 2011, Neuron.

[60]  Kuan-Hung Cho,et al.  Ar Ticle Elevated Expression of Tdp-43 in the Forebrain of Mice Is Sufficient to Cause Neurological and Pathological Phenotypes Mimicking Ftld-u , 2022 .

[61]  E. Fisher,et al.  Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment , 1997, Mammalian Genome.

[62]  CHMP2B mutants linked to frontotemporal dementia impair maturation of dendritic spines , 2010, Journal of Cell Science.

[63]  F. Saggioro,et al.  Sudan Black B treatment reduces autofluorescence and improves resolution of in situ hybridization specific fluorescent signals of brain sections. , 2010, Histology and histopathology.

[64]  J. Crawley,et al.  Social deficits, stereotypy and early emergence of repetitive behavior in the C58/J inbred mouse strain , 2010, Behavioural Brain Research.

[65]  Olivier Piguet,et al.  Amyotrophic lateral sclerosis and frontotemporal dementia: distinct and overlapping changes in eating behaviour and metabolism , 2016, The Lancet Neurology.

[66]  M. Gurney,et al.  Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. , 1994, Science.

[67]  M. Strong,et al.  Amyotrophic lateral sclerosis: A review of current concepts , 2003, Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases.

[68]  K. Ikeda,et al.  Pick's disease with amyotrophic lateral sclerosis (ALS): report of two autopsy cases and literature review , 1997, Journal of the Neurological Sciences.

[69]  R. Caselli,et al.  Cognitive impairment, frontotemporal dementia, and the motor neuron diseases , 2003, Annals of neurology.

[70]  T. Doetschman,et al.  Targeted Ablation of Plasma Membrane Ca2+-ATPase (PMCA) 1 and 4 Indicates a Major Housekeeping Function for PMCA1 and a Critical Role in Hyperactivated Sperm Motility and Male Fertility for PMCA4* , 2004, Journal of Biological Chemistry.

[71]  Catherine Lomen-Hoerth,et al.  The overlap of amyotrophic lateral sclerosis and frontotemporal dementia , 2002, Neurology.

[72]  Xun Hu,et al.  Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6 , 2009, Science.

[73]  J. Loeffler,et al.  Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[74]  J. Collinge,et al.  Progressive neuronal inclusion formation and axonal degeneration in CHMP2B mutant transgenic mice. , 2012, Brain : a journal of neurology.

[75]  L. H. van den Berg,et al.  Genetic Overlap between Apparently Sporadic Motor Neuron Diseases , 2012, PloS one.