TDP-43 knockdown causes innate immune activation via protein kinase R in astrocytes.

Abstract:

:TAR-DNA binding protein 43 (TDP-43) is a multifunctional RNA binding protein directly implicated in the etiology of amyotrophic lateral sclerosis (ALS). Previous studies have demonstrated that loss of TDP-43 function leads to intracellular accumulation of non-coding repetitive element transcripts and double-stranded RNA (dsRNA). These events could cause immune activation and contribute to the neuroinflammation observed in ALS, but this possibility has not been investigated. Here, we knock down TDP-43 in primary rat astrocytes via siRNA, and we use RNA-seq, immunofluorescence, and immunoblotting to show that this results in: 1) accumulation of repetitive element transcripts and dsRNA; and 2) pro-inflammatory gene and protein expression consistent with innate immune signaling and astrocyte activation. We also show that both chemical inhibition and siRNA knockdown of protein kinase R (PKR), a dsRNA-activated kinase implicated in the innate immune response, block the expression of all activation markers assayed. Based on these findings, we suggest that intracellular accumulation of endogenous dsRNA may be a novel and important mechanism underlying the pathogenesis of ALS (and perhaps other neurodegenerative diseases), and that PKR inhibitors may have the potential to prevent reactive astrocytosis in ALS.

journal_name

Neurobiol Dis

journal_title

Neurobiology of disease

authors

LaRocca TJ,Mariani A,Watkins LR,Link CD

doi

10.1016/j.nbd.2019.104514

subject

Has Abstract

pub_date

2019-12-01 00:00:00

pages

104514

eissn

0969-9961

issn

1095-953X

pii

S0969-9961(19)30173-1

journal_volume

132

pub_type

杂志文章
  • Genetically determined susceptibility to neurodegeneration is associated with expression of inflammatory genes.

    abstract::Axonal damage, a core feature of neurological diseases, induces a retrograde reaction in neurons and surrounding glia. We determined transcriptional profiles of this reaction using Affymetrix oligonucleotide arrays. Gene expression was examined in spinal cord tissue prior to injury and following ventral root avulsion ...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2006.05.016

    authors: Swanberg M,Duvefelt K,Diez M,Hillert J,Olsson T,Piehl F,Lidman O

    更新日期:2006-10-01 00:00:00

  • Increased misfolding and truncation of tau in APP/PS1/tau transgenic mice compared to mutant tau mice.

    abstract::Neurofibrillary degeneration in transgenic models of tauopathies has been observed to be enhanced when these models are crossed with transgenic models developing an Aβ pathology. The mechanisms leading to this enhanced tau pathology are not well understood. We have performed a detailed analysis of tau misprocessing in...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2013.09.010

    authors: Héraud C,Goufak D,Ando K,Leroy K,Suain V,Yilmaz Z,De Decker R,Authelet M,Laporte V,Octave JN,Brion JP

    更新日期:2014-02-01 00:00:00

  • Deep brain stimulation in the treatment of refractory epilepsy: update on current data and future directions.

    abstract::Deep brain stimulation for epilepsy has garnered attention from epileptologists due to its well-documented success in treating movement disorders and the low morbidity associated with the implantation of electrodes. Given the large proportion of patients who fail medical therapy and are not candidates for surgical ame...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章,评审

    doi:10.1016/j.nbd.2009.07.007

    authors: Lega BC,Halpern CH,Jaggi JL,Baltuch GH

    更新日期:2010-06-01 00:00:00

  • Neuromodulation targets pathological not physiological beta bursts during gait in Parkinson's disease.

    abstract::Freezing of gait (FOG) is a devastating axial motor symptom in Parkinson's disease (PD) leading to falls, institutionalization, and even death. The response of FOG to dopaminergic medication and deep brain stimulation (DBS) is complex, variable, and yet to be optimized. Fundamental gaps in the knowledge of the underly...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2018.09.004

    authors: Anidi C,O'Day JJ,Anderson RW,Afzal MF,Syrkin-Nikolau J,Velisar A,Bronte-Stewart HM

    更新日期:2018-12-01 00:00:00

  • Subtle microstructural changes of the striatum in a DYT1 knock-in mouse model of dystonia.

    abstract::The dystonias are comprised of a group of disorders that share common neurological abnormalities of involuntary twisting or repetitive movements and postures. The most common inherited primary dystonia is DYT1 dystonia, which is due to loss of a GAG codon in the TOR1A gene that encodes torsinA. Autopsy studies of brai...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2013.01.008

    authors: Song CH,Bernhard D,Bolarinwa C,Hess EJ,Smith Y,Jinnah HA

    更新日期:2013-06-01 00:00:00

  • Putative glucosensing property in rat and human activated microglia.

    abstract::Microglial cells involved in the pathogenesis of many neurodegenerative diseases acquire the features of cytotoxic and phagocytic cells in response to certain pathogens and inflammatory signals. K(ATP) channels are energy sensors of ATP availability that link the cell's metabolic state to its membrane excitability. In...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2003.11.019

    authors: Ramonet D,Rodríguez MJ,Pugliese M,Mahy N

    更新日期:2004-10-01 00:00:00

  • Apolipoprotein E-low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner.

    abstract::Human apolipoprotein E (apoE) exists in three isoforms: apoE2, apoE3 and apoE4. APOE ε4 is a major genetic risk factor for cardiovascular disease (CVD) and Alzheimer's disease (AD). ApoE mediates cholesterol metabolism by binding various receptors. The low-density lipoprotein receptor (LDLR) has a high affinity for ap...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2013.12.016

    authors: Johnson LA,Olsen RH,Merkens LS,DeBarber A,Steiner RD,Sullivan PM,Maeda N,Raber J

    更新日期:2014-04-01 00:00:00

  • Quantitative ultrasound and apoptotic death in the neonatal primate brain.

    abstract::Apoptosis is triggered in the developing mammalian brain by sedative, anesthetic or antiepileptic drugs during late gestation and early life. Whether human children are vulnerable to this toxicity mechanism remains unknown, as there are no imaging techniques to capture it. Apoptosis is characterized by distinct struct...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2019.03.032

    authors: Rosado-Mendez IM,Noguchi KK,Castañeda-Martinez L,Kirvassilis G,Wang SH,Manzella F,Swiney BS,Masuoka K,Capuano S III2,Brunner KG,Crosno K,Guerrero QW,Whitson H,Brambrink A,Simmons HS,Mejia AF,Zagzebski JA,Hall TJ,Ikono

    更新日期:2019-07-01 00:00:00

  • MicroRNA dysregulation in schizophrenia.

    abstract::Schizophrenia is a complex neuropsychiatric disorder that involves disturbances in neural circuitry and synaptic function. The exquisite network architecture and capacity for discreet post-synaptic remodeling of neurons requires coordination by an elaborate intracellular network of molecular signal transduction system...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章,评审

    doi:10.1016/j.nbd.2011.12.029

    authors: Beveridge NJ,Cairns MJ

    更新日期:2012-05-01 00:00:00

  • Mechanisms leading to disseminated apoptosis following NMDA receptor blockade in the developing rat brain.

    abstract::The developing rodent brain is vulnerable to pharmacological blockade of N-methyl-d-aspartate (NMDA) receptors which can lead to severe and disseminated apoptotic neurodegeneration. Here, we show that systemic administration of the NMDA receptor antagonist MK801 to 7-day-old rats leads to impaired activity of extracel...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2004.03.013

    authors: Hansen HH,Briem T,Dzietko M,Sifringer M,Voss A,Rzeski W,Zdzisinska B,Thor F,Heumann R,Stepulak A,Bittigau P,Ikonomidou C

    更新日期:2004-07-01 00:00:00

  • Gentamicin treatment in exercised mdx mice: Identification of dystrophin-sensitive pathways and evaluation of efficacy in work-loaded dystrophic muscle.

    abstract::Aminoglycosides force read through of premature stop codon mutations and introduce new mutation-specific gene-corrective strategies in Duchenne muscular dystrophy. A chronic treatment with gentamicin (32 mg/kg/daily i.p., 8-12 weeks) was performed in exercised mdx mice with the dual aim to clarify the dependence on dy...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2008.07.009

    authors: De Luca A,Nico B,Rolland JF,Cozzoli A,Burdi R,Mangieri D,Giannuzzi V,Liantonio A,Cippone V,De Bellis M,Nicchia GP,Camerino GM,Frigeri A,Svelto M,Camerino DC

    更新日期:2008-11-01 00:00:00

  • Dap12 and Trem2, molecules involved in innate immunity and neurodegeneration, are co-expressed in the CNS.

    abstract::Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is a recessively inherited disease characterized by early onset dementia associated with bone cysts. Our group has recently established the molecular background of PLOSL by identifying mutations in DAP12 and TREM2 genes. To understand...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2004.09.007

    authors: Kiialainen A,Hovanes K,Paloneva J,Kopra O,Peltonen L

    更新日期:2005-03-01 00:00:00

  • Delayed administration of high dose human immunoglobulin G enhances recovery after traumatic cervical spinal cord injury by modulation of neuroinflammation and protection of the blood spinal cord barrier.

    abstract:BACKGROUND/INTRODUCTION:The neuroinflammatory response plays a major role in the secondary injury cascade after traumatic spinal cord injury (SCI). To date, systemic anti-inflammatory medications such as methylprednisolone sodium succinate (MPSS) have shown promise in SCI. However, systemic immunosuppression can have d...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2020.105187

    authors: Chio JCT,Wang J,Surendran V,Li L,Zavvarian MM,Pieczonka K,Fehlings MG

    更新日期:2021-01-01 00:00:00

  • Motor automaticity in Parkinson's disease.

    abstract::Bradykinesia is the most important feature contributing to motor difficulties in Parkinson's disease (PD). However, the pathophysiology underlying bradykinesia is not fully understood. One important aspect is that PD patients have difficulty in performing learned motor skills automatically, but this problem has been g...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章,评审

    doi:10.1016/j.nbd.2015.06.014

    authors: Wu T,Hallett M,Chan P

    更新日期:2015-10-01 00:00:00

  • Adenovirus-mediated GDNF and CNTF pretreatment protects against striatal injury following transient middle cerebral artery occlusion in mice.

    abstract::During the last few years, adenoviral gene transfer techniques have achieved increasing interest in the treatment of neurodegenerative diseases. However, gene therapy requires that delivered genes are translated into proteins. This may pose a problem in focal ischemia where protein synthesis is compromized. The presen...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1006/nbdi.2001.0399

    authors: Hermann DM,Kilic E,Kügler S,Isenmann S,Bähr M

    更新日期:2001-08-01 00:00:00

  • Vascular tight junction disruption and angiogenesis in spontaneously hypertensive rat with neuroinflammatory white matter injury.

    abstract::Vascular cognitive impairment is a major cause of dementia caused by chronic hypoxia, producing progressive damage to white matter (WM) secondary to blood-brain barrier (BBB) opening and vascular dysfunction. Tight junction proteins (TJPs), which maintain BBB integrity, are lost in acute ischemia. Although angiogenesi...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2018.02.012

    authors: Yang Y,Kimura-Ohba S,Thompson JF,Salayandia VM,Cossé M,Raz L,Jalal FY,Rosenberg GA

    更新日期:2018-06-01 00:00:00

  • Effects of chronic network hyperexcitability on the growth of hippocampal dendrites.

    abstract::Experiments reported here were motivated by studies in both human epilepsy and animal models in which stunted dendritic arbors are observed. Our goal was to determine if chronic network hyperexcitability alters dendritic growth. Experiments were conducted in hippocampal slice cultures obtained from infant mice that ex...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2007.08.018

    authors: Nishimura M,Owens J,Swann JW

    更新日期:2008-02-01 00:00:00

  • Acute exposure to GSM 900-MHz electromagnetic fields induces glial reactivity and biochemical modifications in the rat brain.

    abstract::The worldwide proliferation of mobile phones raises the question of the effects of 900-MHz electromagnetic fields (EMF) on the brain. Using a head-only exposure device in the rat, we showed that a 15-min exposure to 900-MHz pulsed microwaves at a high brain-averaged power of 6 W/kg induced a strong glial reaction in t...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2004.07.004

    authors: Mausset-Bonnefont AL,Hirbec H,Bonnefont X,Privat A,Vignon J,de Sèze R

    更新日期:2004-12-01 00:00:00

  • Neurochemistry and the non-motor aspects of PD.

    abstract::Parkinson disease (PD) is a systemic disease with variegated non-motor deficits and neurological symptoms, including impaired olfaction, autonomic failure, cognitive impairment and psychiatric symptoms, in addition to the classical motor symptoms. Many non-motor symptoms appear before or in parallel with motor deficit...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章,评审

    doi:10.1016/j.nbd.2011.10.019

    authors: Ferrer I,López-Gonzalez I,Carmona M,Dalfó E,Pujol A,Martínez A

    更新日期:2012-06-01 00:00:00

  • NP03, a novel low-dose lithium formulation, is neuroprotective in the YAC128 mouse model of Huntington disease.

    abstract::Huntington disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene, remains without a treatment to modify the course of the illness. Lithium, a drug widely used for the treatment of bipolar disorder, has been shown to exert neuroprotective effects in a number of models of neurologic...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2012.06.026

    authors: Pouladi MA,Brillaud E,Xie Y,Conforti P,Graham RK,Ehrnhoefer DE,Franciosi S,Zhang W,Poucheret P,Compte E,Maurel JC,Zuccato C,Cattaneo E,Néri C,Hayden MR

    更新日期:2012-12-01 00:00:00

  • PTEN deletion increases hippocampal granule cell excitability in male and female mice.

    abstract::Deletion of the mTOR pathway inhibitor PTEN from postnatally-generated hippocampal dentate granule cells causes epilepsy. Here, we conducted field potential, whole cell recording and single cell morphology studies to begin to elucidate the mechanisms by which granule cell-specific PTEN-loss produces disease. Cells fro...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2017.08.014

    authors: Santos VR,Pun RYK,Arafa SR,LaSarge CL,Rowley S,Khademi S,Bouley T,Holland KD,Garcia-Cairasco N,Danzer SC

    更新日期:2017-12-01 00:00:00

  • Identification of a unique apolipoprotein E allele in Microcebus murinus; ApoE brain distribution and co-localization with beta-amyloid and tau proteins.

    abstract::This report is devoted to the characterization of the apolipoprotein E (ApoE) in Microcebus murinus. Only one allele homologous to the human ApoE4 allele was evidenced. The distribution of the corresponding ApoE protein in the brain was found in association with the pathological proteins characteristic of Alzheimer's ...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1006/nbdi.1995.0018

    authors: Calenda A,Jallageas V,Silhol S,Bellis M,Bons N

    更新日期:1995-06-01 00:00:00

  • Identification of an acute functional cross-talk between amyloid-β and glucocorticoid receptors at hippocampal excitatory synapses.

    abstract::Amyloid-β is a peptide released by synapses in physiological conditions and its pathological accumulation in brain structures necessary for memory processing represents a key toxic hallmark underlying Alzheimer's disease. The oligomeric form of Amyloid-β (Aβο) is now believed to represent the main Amyloid-β species af...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2018.07.001

    authors: Kootar S,Frandemiche ML,Dhib G,Mouska X,Lorivel T,Poupon-Silvestre G,Hunt H,Tronche F,Bethus I,Barik J,Marie H

    更新日期:2018-10-01 00:00:00

  • The ins and outs of a polyglutamine neurodegenerative disease: spinocerebellar ataxia type 1 (SCA1).

    abstract::Polyglutamine neurodegenerative disorders are characterized by the expansion of a glutamine tract within the mutant disease-causing protein. Expression of the mutant protein induces a progressive loss of neuronal function and the subsequent neurodegeneration of a set of neurons characteristic to each disease. Spinocer...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章,评审

    doi:10.1006/nbdi.2000.0305

    authors: Orr HT

    更新日期:2000-06-01 00:00:00

  • EphrinB1 and EphrinB2 regulate T cell chemotaxis and migration in experimental autoimmune encephalomyelitis and multiple sclerosis.

    abstract::T cells are believed to be key effector cells in multiple sclerosis (MS). In this study, we examined the roles of T cell ephrinB1 (EFNB1) and ephrinB2 (EFNB2) in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and MS. We provide evidence that animals with T cell specific double deletion of EFNB1 an...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2016.03.013

    authors: Luo H,Broux B,Wang X,Hu Y,Ghannam S,Jin W,Larochelle C,Prat A,Wu J

    更新日期:2016-07-01 00:00:00

  • AGS-induced expression of Narp is concomitant with expression of AMPA receptor subunits GluR1 and GluR2 in hippocampus but not inferior colliculus of P77PMC rats.

    abstract::To explore mechanisms of epileptogenesis in audiogenic seizures (AGS), we examined the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazoleopropionic acid (AMPA) receptor subunits GluR1 and GluR2 and of the GluR-associated protein Narp in the hippocampus and the inferior colliculus (IC) from AGS-susceptible P77PMC...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2003.08.010

    authors: Li SY,Xu DS,Jia HT

    更新日期:2003-12-01 00:00:00

  • Amyloid-beta peptide is toxic to neurons in vivo via indirect mechanisms.

    abstract::We have studied the neurotoxicity of amyloid-beta (Abeta) after a single unilateral intravitreal injection. Within the retina apoptotic cells were seen throughout the photoreceptor layer and the inner nuclear layer but not in the ganglion cell layer at 48 h after injection of Abeta(1-42) compared to vehicle control an...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1006/nbdi.2002.0485

    authors: Walsh DT,Montero RM,Bresciani LG,Jen AY,Leclercq PD,Saunders D,EL-Amir AN,Gbadamoshi L,Gentleman SM,Jen LS

    更新日期:2002-06-01 00:00:00

  • High-fructose intake as risk factor for neurodegeneration: Key role for carboxy methyllysine accumulation in mice hippocampal neurons.

    abstract::Several studies indicate the involvement of advanced glycation end-products (AGEs) in neurodegenerative diseases. Moreover, the rising consumption of fructose in industrialized countries has been related to cognitive impairment, but the impact of fructose-derived AGEs on hippocampus has never been investigated. The pr...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2016.02.005

    authors: Mastrocola R,Nigro D,Cento AS,Chiazza F,Collino M,Aragno M

    更新日期:2016-05-01 00:00:00

  • Elevated plasma triglyceride levels precede amyloid deposition in Alzheimer's disease mouse models with abundant A beta in plasma.

    abstract::Dietary or pharmacological manipulation of plasma lipids markedly influences amyloid deposition in animal models of Alzheimer's Disease (AD). However, it is not known whether baseline plasma lipids in AD models differ from wild-type littermates throughout the natural history of disease. To address this question, we me...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2006.06.007

    authors: Burgess BL,McIsaac SA,Naus KE,Chan JY,Tansley GH,Yang J,Miao F,Ross CJ,van Eck M,Hayden MR,van Nostrand W,St George-Hyslop P,Westaway D,Wellington CL

    更新日期:2006-10-01 00:00:00

  • Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice.

    abstract::Mutations in the LRRK2 gene represent the most common genetic cause of late onset Parkinson's disease. The physiological and pathological roles of LRRK2 are yet to be fully determined but evidence points towards LRRK2 mutations causing a gain in kinase function, impacting on neuronal maintenance, vesicular dynamics an...

    journal_title:Neurobiology of disease

    pub_type: 杂志文章

    doi:10.1016/j.nbd.2015.02.031

    authors: Yue M,Hinkle KM,Davies P,Trushina E,Fiesel FC,Christenson TA,Schroeder AS,Zhang L,Bowles E,Behrouz B,Lincoln SJ,Beevers JE,Milnerwood AJ,Kurti A,McLean PJ,Fryer JD,Springer W,Dickson DW,Farrer MJ,Melrose HL

    更新日期:2015-06-01 00:00:00