- •The RNA binding protein hnRNP A1 is dysfunctional in MS.
- •IFNγ contributes to hnRNP A1 dysfunction.
- •Neurons in MS brain show pathogenic features of hnRNP A1 dysfunction.
- •The features include hnRNP A1 nuclear depletion & colocalization in cytoplasmic stress granules.
Dysfunction of the RNA binding protein (RBP) heterogeneous nuclear ribonuclear protein A1 (hnRNP A1) has been shown to contribute to the pathogenesis of neurodegenerative diseases, but its involvement in multiple sclerosis (MS) is largely unknown. In a neuronal cell line, interferon-γ caused hnRNP A1 nucleocytoplasmic mislocalization; colocalization of hnRNP A1 in stress granules (SGs); and inhibition of translation. Neurons in the brain of a MS patient showed pathogenic RBP dysfunction, including nuclear depletion of hnRNP A1, its mislocalization to the cytoplasm, and its colocalization in SGs. These data indicate a role for dysfunctional hnRNP A1 in the pathogenesis of MS.
Abbreviations:ALS (amyotrophic lateral sclerosis), FTLD (frontotemporal lobar degeneration), FUS (fused in sarcoma), hnRNP A1 (heterogeneous nuclear ribonucleoprotein A1), IFNγ (interferon gamma), IL-12 (interleukin-12), MS (Multiple sclerosis), RBP (RNA binding protein), SG (stress granule), TDP-43 (TAR-DNA binding protein 43), TGF-β (transforming growth factor-beta), TIA1 (T-cell restricted intracellular antigen-1)
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Journal of Neuroimmunology
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Cytokines and acute neurodegeneration.Nat. Rev. Neurosci. 2001; 2: 734-744
- Stress granules.Curr. Biol. 2009; 19: R397-R398
- Stage-specific role of interferon-gamma in experimental autoimmune encephalomyelitis and multiple sclerosis.Front. Immunol. 2015; 6: 492
- G3BP1 promotes stress-induced RNA granule interactions to preserve polyadenylated mRNA.J. Cell Biol. 2015; 209: 73-84
- Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestation in multiple sclerosis: do cytokines trigger off exacerbations?.Acta Neurol. Scand. 1988; 78: 318-323
- Requirements for stress granule recruitment of fused in sarcoma (FUS) and TAR DNA-binding protein of 43 kDa (TDP-43).J. Biol. Chem. 2012; 287: 23079-23094
- The cell diversity in experimental autoimmune encephalomyelitis and multiple sclerosis.J. Immunol. 2015; 195: 2552-2559
- TDP-43 is recruited to stress granules in conditions of oxidative insult.J. Neurochem. 2009; 111: 1051-1061
- The role of FUS gene variants in neurodegenerative diseases.Nat. Rev. Neurol. 2014; 10: 337-348
- TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor.Mol. Cell. Biol. 2011; 31: 1098-1108
- Antibodies to the RNA-binding protein hnRNP A1 contribute to neurodegeneration in a model of central nervous system autoimmune inflammatory disease.J. Neuroinflammation. 2016; 13: 178
- The relation between inflammation and neurodegeneration in multiple sclerosis brains.Brain. 2009; 132: 1175-1189
- Multiple sclerosis - the plaque and its pathogenesis.NEJM. 2006; 354: 942-955
- Pattern of axonal injury in murine myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis: implications for multiple sclerosis.Neurobiol. Dis. 2008; 30: 162-173
- Stress granule formation mediates the inhibition of colonic Hsp70 translation by interferon-γ and tumor necrosis factor-α.Am. J. Physiol. Gastrointest. Liver Physiol. 2010; 298: G481-G492
- Induction of stress granules by interferon and down-regulation by the cellular RNA adenosine deaminase ADAR1.Virology. 2014; 454-455: 299-310
- Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS.Nature. 2013; 495: 467-473
- Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions.Am. J. Pathol. 2000; 157: 267-276
- Cortical demyelination and diffuse white matter injury in multiple sclerosis.Brain. 2005; 128: 2705-2712
- TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration.Hum. Mol. Genet. 2010; 19: R46-R64
- The molecular basis of neurodegeneration in multiple sclerosis.FEBS Lett. 2011; 585: 3715-3723
- A potential link between autoimmunity and neurodegeneration in immune-mediated neurological disease.J. Neuroimmunol. 2011; 235: 56-69
- Autoimmunity due to molecular mimicry as a cause of neurological disease.Nat. Med. 2002; 8: 509-513
- Stress granules as crucibles of ALS pathogenesis.J. Cell Biol. 2013; 201: 361-372
- Endoplasmic reticulum stress modulates the response of myelinating oligodendrocytes to the immune cytokine interferon-gamma.J. Cell Biol. 2005; 169: 603-612
- Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis.Neuron. 2013; 79: 416-438
- Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue.PLoS One. 2010; 5e13250
- TIA1 mutations in amyotrophic lateral sclerosis and frontotemporal dementia promote phase separation and alter stress granule dynamics.Neuron. 2017; 95 (e9): 808-816
- A Gradient of neuronal loss and meningeal inflammation in multiple sclerosis.Ann. Neurol. 2010; 68: 477-493
- Cytoplasmic stress granules: Dynamic modulators of cell signaling and disease.Biochim. Biophys. Acta. 2017; 1863: 884-895
- Dysregulation of RNA binding protein aggregation in neurodegenerative disorders.Front. Mol. Neurosci. 2017; 10: 89
- Interferon-gamma directly induces neurotoxicity through a neuron specific, calcium-permeable complex of IFN-gamma receptor and AMPA GluR1 receptor.FASEB J. 2008; 22: 1797-1806
- Linking hnRNP function to ALS and FTD pathology.Front. Neurosci. 2018; 12: 326
- Altered ribostasis: RNA-protein granules in degenerative disorders.Cell. 2013; 154: 727-736
- Contrasting pathology of the stress granule proteins TIA-1 and G3BP in tauopathies.J. Neurosci. 2012; 32: 8270-8283
- Physiological protein aggregation run amuck: stress granules and the genesis of neurodegenerative disease.Discov. Med. 2014; 17: 47-52
Published online: August 29, 2018
Accepted: August 28, 2018
Received in revised form: August 27, 2018
Received: August 8, 2018
© 2018 Published by Elsevier B.V.