TDP-43 Vasculopathy in the Spinal Cord in Sporadic Amyotrophic Lateral Sclerosis (sALS) and Frontal Cortex in sALS/FTLD-TDP

Abstract Sporadic amyotrophic lateral sclerosis (sALS) and FTLD-TDP are neurodegenerative diseases within the spectrum of TDP-43 proteinopathies. Since abnormal blood vessels and altered blood-brain barrier have been described in sALS, we wanted to know whether TDP-43 pathology also occurs in blood vessels in sALS/FTLD-TDP. TDP-43 deposits were identified in association with small blood vessels of the spinal cord in 7 of 14 cases of sALS and in small blood vessels of frontal cortex area 8 in 6 of 11 FTLD-TDP and sALS cases, one of them carrying a GRN mutation. This was achieved using single and double-labeling immunohistochemistry, and double-labeling immunofluorescence and confocal microscopy. In the sALS spinal cord, P-TDP43 Ser403-404 deposits were elongated and parallel to the lumen, whereas others were granular, seldom forming clusters. In the frontal cortex, the inclusions were granular, or elongated and parallel to the lumen, or forming small globules within or in the external surface of the blood vessel wall. Other deposits were localized in the perivascular space. The present findings are in line with previous observations of TDP-43 vasculopathy in a subset of FTLD-TDP cases and identify this pathology in the spinal cord and frontal cortex in a subset of cases within the sALS/FTLD-TDP spectrum.

[1]  F. Fornai,et al.  Chronic stress induces formation of stress granules and pathological TDP-43 aggregates in human ALS fibroblasts and iPSC-motoneurons , 2020, Neurobiology of Disease.

[2]  L. Zolla,et al.  ALS skin fibroblasts reveal oxidative stress and ERK1/2-mediated cytoplasmic localization of TDP-43. , 2020, Cellular signalling.

[3]  M. Berciano,et al.  ALS-derived fibroblasts exhibit reduced proliferation rate, cytoplasmic TDP-43 aggregation and a higher susceptibility to DNA damage , 2020, Journal of Neurology.

[4]  S. Cavallaro,et al.  A novel S379A TARDBP mutation associated to late-onset sporadic ALS , 2019, Neurological Sciences.

[5]  Yu-Long Lan,et al.  The potential roles of aquaporin 4 in amyotrophic lateral sclerosis , 2019, Neurological Sciences.

[6]  I. Ferrer,et al.  Gene Expression Profile in Frontal Cortex in Sporadic Frontotemporal Lobar Degeneration-TDP , 2018, Journal of neuropathology and experimental neurology.

[7]  I. Ferrer,et al.  Inflammatory Gene Expression in Whole Peripheral Blood at Early Stages of Sporadic Amyotrophic Lateral Sclerosis , 2017, Front. Neurol..

[8]  Z. Modrušan,et al.  Progranulin deficiency causes impairment of autophagy and TDP-43 accumulation , 2017, The Journal of experimental medicine.

[9]  C. Duyckaerts,et al.  Amygdala TDP-43 Pathology in Frontotemporal Lobar Degeneration and Motor Neuron Disease , 2017, Journal of neuropathology and experimental neurology.

[10]  I. Ferrer,et al.  Amyotrophic lateral sclerosis, gene deregulation in the anterior horn of the spinal cord and frontal cortex area 8: implications in frontotemporal lobar degeneration , 2017, Aging.

[11]  G. Rouleau,et al.  ALS: Recent Developments from Genetics Studies , 2016, Current Neurology and Neuroscience Reports.

[12]  S. Sasaki.  Alterations of the blood‐spinal cord barrier in sporadic amyotrophic lateral sclerosis , 2015, Neuropathology : official journal of the Japanese Society of Neuropathology.

[13]  G. Sobue,et al.  Alterations in the blood–spinal cord barrier in TDP-43 conditional knockout mice , 2015, Neuroscience Letters.

[14]  Daniel R. Schonhaut,et al.  A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques , 2015, Acta neuropathologica communications.

[15]  S. Sakoda,et al.  Microvascular disturbance with decreased pericyte coverage is prominent in the ventral horn of patients with amyotrophic lateral sclerosis , 2015, Amyotrophic lateral sclerosis & frontotemporal degeneration.

[16]  Pavel Ivanov,et al.  tRNA fragments in human health and disease , 2014, FEBS letters.

[17]  C. van Broeckhoven,et al.  TARDBP mutation p.Ile383Val associated with semantic dementia and complex proteinopathy , 2014, Neuropathology and applied neurobiology.

[18]  Christian Haass,et al.  Stress granules in neurodegeneration – lessons learnt from TAR DNA binding protein of 43 kDa and fused in sarcoma , 2013, The FEBS journal.

[19]  L. Petrucelli,et al.  RNA-mediated toxicity in neurodegenerative disease , 2013, Molecular and Cellular Neuroscience.

[20]  J. Kril,et al.  Classification of FTLD-TDP cases into pathological subtypes using antibodies against phosphorylated and non-phosphorylated TDP43 , 2013, Acta neuropathologica communications.

[21]  C. Shaw,et al.  Drosophila TDP-43 dysfunction in glia and muscle cells cause cytological and behavioural phenotypes that characterize ALS and FTLD , 2013, Human molecular genetics.

[22]  E. Kremmer,et al.  Loss of ALS-associated TDP-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth , 2013, Proceedings of the National Academy of Sciences.

[23]  D. Leys,et al.  Detection of microbleeds in post‐mortem brains of patients with frontotemporal lobar degeneration: a 7.0‐Tesla magnetic resonance imaging study with neuropathological correlates , 2012, European journal of neurology.

[24]  Jesse D. Sengillo,et al.  Blood–spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis , 2012, Acta Neuropathologica.

[25]  Paul R. Sanberg,et al.  Impaired blood–brain/spinal cord barrier in ALS patients , 2012, Brain Research.

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

[27]  J. Trojanowski,et al.  On the development of markers for pathological TDP-43 in amyotrophic lateral sclerosis with and without dementia , 2011, Progress in Neurobiology.

[28]  J. Trojanowski,et al.  TDP-43 functions and pathogenic mechanisms implicated in TDP-43 proteinopathies. , 2011, Trends in molecular medicine.

[29]  T. Hortobágyi,et al.  Amyotrophic Lateral Sclerosis, Primary Lateral Sclerosis and Spinal Muscular Atrophy , 2011 .

[30]  Charles D. Smith,et al.  The Multiple Faces of Valosin-Containing Protein-Associated Diseases: Inclusion Body Myopathy with Paget’s Disease of Bone, Frontotemporal Dementia, and Amyotrophic Lateral Sclerosis , 2011, Journal of Molecular Neuroscience.

[31]  S. Kumar-Singh.  Progranulin and TDP-43: Mechanistic Links and Future Directions , 2011, Journal of Molecular Neuroscience.

[32]  P. Sanberg,et al.  Amyotrophic lateral sclerosis: A neurovascular disease , 2011, Brain Research.

[33]  J. Trojanowski,et al.  A harmonized classification system for FTLD-TDP pathology , 2011, Acta Neuropathologica.

[34]  K. Abe,et al.  Disruption of neurovascular unit prior to motor neuron degeneration in amyotrophic lateral sclerosis , 2011, Journal of neuroscience research.

[35]  J. Ule,et al.  Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. , 2011, Nature neuroscience.

[36]  M. Cynader,et al.  Progranulin deficiency leads to enhanced cell vulnerability and TDP-43 translocation in primary neuronal cultures , 2010, Brain Research.

[37]  L. Petrucelli,et al.  Tar DNA Binding Protein-43 (TDP-43) Associates with Stress Granules: Analysis of Cultured Cells and Pathological Brain Tissue , 2010, PloS one.

[38]  V. Meininger,et al.  SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype–phenotype correlations , 2010, Journal of Medical Genetics.

[39]  E. Buratti,et al.  Nuclear factor TDP‐43 can affect selected microRNA levels , 2010, The FEBS journal.

[40]  D. Cleveland,et al.  TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. , 2010, Human molecular genetics.

[41]  M. Piccinini,et al.  TDP‐43 Redistribution is an Early Event in Sporadic Amyotrophic Lateral Sclerosis , 2010, Brain pathology.

[42]  I. Niebroj-Dobosz,et al.  Matrix metalloproteinases and their tissue inhibitors in serum and cerebrospinal fluid of patients with amyotrophic lateral sclerosis , 2010, European journal of neurology.

[43]  Zhi-ying Wu,et al.  Association between novel TARDBP mutations and Chinese patients with amyotrophic lateral sclerosis , 2010, BMC Medical Genetics.

[44]  S. Finkbeiner,et al.  Cytoplasmic Mislocalization of TDP-43 Is Toxic to Neurons and Enhanced by a Mutation Associated with Familial Amyotrophic Lateral Sclerosis , 2010, The Journal of Neuroscience.

[45]  M. Strong,et al.  Tar DNA binding protein of 43 kDa (TDP-43), 14-3-3 proteins and copper/zinc superoxide dismutase (SOD1) interact to modulate NFL mRNA stability. Implications for altered RNA processing in amyotrophic lateral sclerosis (ALS) , 2009, Brain Research.

[46]  D. Dickson,et al.  Transactivation Response DNA-Binding Protein 43 Microvasculopathy in Frontotemporal Degeneration and Familial Lewy Body Disease , 2009, Journal of neuropathology and experimental neurology.

[47]  B. Ghetti,et al.  TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea , 2009, Movement disorders : official journal of the Movement Disorder Society.

[48]  J. Morris,et al.  TARDBP 3′-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy , 2009, Acta Neuropathologica.

[49]  R. Bowser,et al.  DECREASED mRNA EXPRESSION OF TIGHT JUNCTION PROTEINS IN LUMBAR SPINAL CORDS OF PATIENTS WITH ALS , 2009, Neurology.

[50]  M. Farrer,et al.  Pallidonigral TDP-43 pathology in Perry syndrome. , 2009, Parkinsonism & related disorders.

[51]  Isidre Ferrer,et al.  TAR DNA-Binding Protein 43 Accumulation in Protein Aggregate Myopathies , 2009, Journal of neuropathology and experimental neurology.

[52]  John L. Robinson,et al.  Clinical and pathological continuum of multisystem TDP-43 proteinopathies. , 2009, Archives of neurology.

[53]  N. Cairns,et al.  Fine structural analysis of the neuronal inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy , 2008, Journal of Neural Transmission.

[54]  A. Pestronk,et al.  TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia , 2008, Journal of Neurology, Neurosurgery, and Psychiatry.

[55]  Hitoshi Takahashi,et al.  Maturation process of TDP-43-positive neuronal cytoplasmic inclusions in amyotrophic lateral sclerosis with and without dementia , 2008, Acta Neuropathologica.

[56]  K. Okamoto,et al.  Anterior horn cells with abnormal TDP-43 immunoreactivities show fragmentation of the Golgi apparatus in ALS , 2008, Journal of the Neurological Sciences.

[57]  I-Fan Wang,et al.  TDP‐43, the signature protein of FTLD‐U, is a neuronal activity‐responsive factor , 2008, Journal of neurochemistry.

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

[59]  M. Grossman,et al.  Motor Neuron Disease and Frontotemporal Lobar Degeneration: A Tale of Two Disorders Linked To TDP-43 , 2007, Neurosignals.

[60]  J. Trojanowski,et al.  Severe subcortical TDP-43 pathology in sporadic frontotemporal lobar degeneration with motor neuron disease , 2007, Acta Neuropathologica.

[61]  L. Petrucelli,et al.  Progranulin Mediates Caspase-Dependent Cleavage of TAR DNA Binding Protein-43 , 2007, The Journal of Neuroscience.

[62]  J. Morris,et al.  TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. , 2007, The American journal of pathology.

[63]  D. Dickson,et al.  TDP-43 in differential diagnosis of motor neuron disorders , 2007, Acta Neuropathologica.

[64]  J. Molinuevo,et al.  Late-onset frontotemporal dementia associated with a novel PGRN mutation , 2007, Journal of neural transmission.

[65]  Murray Grossman,et al.  TDP-43-Positive White Matter Pathology in Frontotemporal Lobar Degeneration With Ubiquitin-Positive Inclusions , 2007, Journal of neuropathology and experimental neurology.

[66]  D. Neary,et al.  Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43 , 2007, Acta Neuropathologica.

[67]  Bruce L. Miller,et al.  Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis , 2006, Science.

[68]  J. Trojanowski,et al.  Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies. , 2006, The American journal of pathology.

[69]  Julie S. Snowden,et al.  Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype , 2006, Acta Neuropathologica.

[70]  E. Buratti,et al.  TDP-43 Binds Heterogeneous Nuclear Ribonucleoprotein A/B through Its C-terminal Tail , 2005, Journal of Biological Chemistry.

[71]  I. Mackenzie,et al.  Ubiquitin Immunohistochemistry Suggests Classic Motor Neuron Disease, Motor Neuron Disease With Dementia, and Frontotemporal Dementia of the Motor Neuron Disease Type Represent a Clinicopathologic Spectrum , 2005, Journal of neuropathology and experimental neurology.

[72]  A. Petzold,et al.  The pro and the active form of matrix metalloproteinase-9 is increased in serum of patients with amyotrophic lateral sclerosis , 2005, Journal of Neuroimmunology.

[73]  E. Aronica,et al.  Immunohistochemical localization of vascular endothelial growth factor receptors‐1, ‐2 and ‐3 in human spinal cord: altered expression in amyotrophic lateral sclerosis , 2004, Neuropathology and applied neurobiology.

[74]  T. Siddique,et al.  Presence of dendritic cells, MCP‐1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue , 2004, Annals of neurology.

[75]  T. Dörk,et al.  Nuclear factor TDP‐43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping , 2001, The EMBO journal.

[76]  F. Weber,et al.  Matrix metalloproteinase‐9 is elevated in serum of patients with amyotrophic lateral sclerosis , 2000, Neuroreport.

[77]  C. Miller,et al.  Matrix Metalloproteinases in the Neocortex and Spinal Cord of Amyotrophic Lateral Sclerosis Patients , 1996, Journal of neurochemistry.

[78]  S. Appel,et al.  IgG reactivity in the spinal cord and motor cortex in amyotrophic lateral sclerosis. , 1990, Archives of neurology.

[79]  R. Kascsak,et al.  Deposits of IgG and C3 in the spinal cord and motor cortex of ALS patients , 1984, Journal of Neuroimmunology.

[80]  M. Beckerman.  Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration , 2015 .

[81]  M. Itokawa,et al.  TDP-43 M337V mutation in familial amyotrophic lateral sclerosis in Japan. , 2010, Internal medicine.

[82]  J. Tajti,et al.  Lymphocytic infiltrates in the spinal cord in amyotrophic lateral sclerosis. , 1993, Archives of neurology.