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Multiple Sclerosis-Associated Hnrnpa1 Mutations Alter Hnrnpa1 Dynamics and Influence Stress Granule Formation

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Multiple Sclerosis-Associated Hnrnpa1 Mutations Alter Hnrnpa1 Dynamics and Influence Stress Granule Formation International Journal of Molecular Sciences Article Multiple Sclerosis-Associated hnRNPA1 Mutations Alter hnRNPA1 Dynamics and Influence Stress Granule Formation Joseph-Patrick W. E. Clarke 1,2,* , Patricia A. Thibault 2,3, Hannah E. Salapa 2,3 , David E. Kim 4, Catherine Hutchinson 2,3 and Michael C. Levin 1,2,3,4,* 1 Department of Health Sciences, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada 2 Office of the Saskatchewan Multiple Sclerosis Clinical Research Chair, University of Saskatchewan, Saskatoon, SK S7K 0M7, Canada; [email protected] (P.A.T.); [email protected] (H.E.S.); [email protected] (C.H.) 3 Department of Medicine, Neurology Division, University of Saskatchewan, Saskatoon, SK S7N 0X8, Canada 4 Department of Anatomy, Physiology and Pharmacology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; [email protected] * Correspondence: [email protected] (J.-P.W.E.C.); [email protected] (M.C.L.); Tel.: +1-306-6558 (M.C.L.) Abstract: Evidence indicates that dysfunctional heterogeneous ribonucleoprotein A1 (hnRNPA1; A1) contributes to the pathogenesis of neurodegeneration in multiple sclerosis. Understanding molecular mechanisms of neurodegeneration in multiple sclerosis may result in novel therapies that attenuate neurodegeneration, thereby improving the lives of MS patients with multiple sclerosis. Using an in vitro, blue light induced, optogenetic protein expression system containing the optogene Citation: Clarke, J.-P.W.E.; Thibault, Cryptochrome 2 and a fluorescent mCherry reporter, we examined the effects of multiple sclerosis- P.A.; Salapa, H.E.; Kim, D.E.; associated somatic A1 mutations (P275S and F281L) in A1 localization, cluster kinetics and stress Hutchinson, C.; Levin, M.C. Multiple granule formation in real-time. We show that A1 mutations caused cytoplasmic mislocalization, and Sclerosis-Associated hnRNPA1 significantly altered the kinetics of A1 cluster formation/dissociation, and the quantity and size of Mutations Alter hnRNPA1 Dynamics clusters. A1 mutations also caused stress granule formation to occur more quickly and frequently in and Influence Stress Granule response to blue light stimulation. This study establishes a live cell optogenetics imaging system to Formation. Int. J. Mol. Sci. 2021, 22, probe localization and association characteristics of A1. It also demonstrates that somatic mutations 2909. https://doi.org/10.3390/ in A1 alter its function and promote stress granule formation, which supports the hypothesis that A1 ijms22062909 dysfunction may exacerbate neurodegeneration in multiple sclerosis. Academic Editor: Patrick R. Onck Keywords: hnRNPA1; mutations; optogenetics; stress granules; multiple sclerosis Received: 11 February 2021 Accepted: 9 March 2021 Published: 12 March 2021 1. Introduction Publisher’s Note: MDPI stays neutral Multiple sclerosis (MS) is an autoimmune disease with a significant neurodegenerative with regard to jurisdictional claims in component characterized by inflammation-mediated demyelination of neuronal axons, and published maps and institutional affil- subsequent neurodegenerative axonal and neuronal cell loss [1]. Current research posits a iations. multitude of molecular mechanisms underlying MS-associated neurodegeneration, many of which likely interact to initiate and exacerbate each other. Studies have shown that mito- chondrial injury, microglial activation, reactive oxygen species, and apoptosis contribute to axonal injury [2–8]. Other studies implicate increased energy demands and the reduction Copyright: © 2021 by the authors. of ATP production in axons, resulting in ‘virtual hypoxia’ [9–11]. Neurodegeneration can Licensee MDPI, Basel, Switzerland. also be driven by inflammatory cytokines, autoantibodies, a lack of trophic support from This article is an open access article myelin, glutamate toxicity, endoplasmic stress, altered iron homeostasis, and abnormal distributed under the terms and sodium channel expression on, and calcium accumulation within, damaged axons [12–22]. conditions of the Creative Commons In addition, our lab and others have demonstrated a substantial role for RNA binding Attribution (CC BY) license (https:// protein (RBP) dysfunction, including that of heterogeneous nuclear ribonucleoprotein A1 creativecommons.org/licenses/by/ (hnRNPA1, or A), in the pathogenesis of MS and relevant MS models [9,23–31]. 4.0/). Int. J. Mol. Sci. 2021, 22, 2909. https://doi.org/10.3390/ijms22062909 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 2909 2 of 21 RBPs, including TAR DNA-binding protein 43 (TDP-43), Fused in Sarcoma (FUS) and T-cell-restricted intracellular antigen-1 (TIA1), and A1, function in many facets of RNA metabolism, as well as in other important cellular mechanisms [32–34]. For example, Int. J. Mol. Sci. 2021, 22, 2909 2 of 22 A1 plays a significant role in RNA splicing and RNA nucleocytoplasmic transport to ri- bosomal targets [35,36]. With two N-terminal RNA recognition motifs (RRMs) that bind RNA, it facilitates mRNAnuclear transitribonucleoprotein from nucleus A1 (hnRNPA1, to cytoplasmor A), in the pathogenesis via the M9 of MS nucleocytoplas- and relevant MS models [9,23–31]. mic transport domain foundRBPs, including within TAR its C-terminalDNA-binding protein prion-like 43 (TDP-43), domain Fused in (PrLD)Sarcoma (FUS) (Figure and 1A, schematic) [37–39]. TheT-cell-restricted PrLD of A1 intracellular functions antigen-1 similarly (TIA1), to and that A1, of function other in RBPs many andfacets can of RNA mediate metabolism, as well as in other important cellular mechanisms [32–34]. For example, A1 self- and non-self protein-proteinplays a significant interactions role in RNA splicing [40–44 and]. RNA Reports nucleocytoplasmic from our transport lab have to riboso- proposed that A1 self-interaction,mal mediated targets [35,36]. by With M9 two within N-terminal the PrLDRNA recognition of A1, maymotifs lead(RRMs) to that A1 bind protein RNA, dys- function, and play a roleit facilitates in MS pathogenesismRNA transit from [25 nucleus]. Specifically, to cytoplasm our via labthe hasM9 nucleocytoplasmic previously shown transport domain found within its C-terminal prion-like domain (PrLD) (Figure 1A, sche- the cytoplasmic mislocalizationmatic) [37–39]. ofThe A1 PrLD within of A1 functions neurons simi inlarly the to that brains of other of RBPs MS and patients, can mediate as well as in neurons from anself- MS-like and non-self animal protein-protein model, experimental interactions [40–44]. autoimmune Reports from our encephalomyelitis lab have pro- posed that A1 self-interaction, mediated by M9 within the PrLD of A1, may lead to A1 (EAE) [28–31]. To molecularlyprotein dysfunction, understand and play howa role in A1 MS becomespathogenesis mislocalized [25]. Specifically, our and lab aggregated, has pre- our lab also assessedviously the mutation shown the cytoplasmic profile of mi A1slocalization in cells of fromA1 within MS neurons patients, in the brains and of found MS an accumulation of significantpatients, somatic as well as singlein neurons nucleotide from an MS-like variants animal model, (SNVs) experimental in the PrLD autoimmune of A1 [25]. encephalomyelitis (EAE) [28–31]. To molecularly understand how A1 becomes mislocal- Further characterizationized showed and aggregated, that A1our PrLDlab also mutationsassessed the mutation in the M9profile sequence of A1 in cells induce from MS its mis- localization by prohibitingpatients, Transportin and found an 1accumulation (TNPO1) of from significant properly somatic binding single nucleotide to the variants M9 region (SNVs) in the PrLD of A1 [25]. Further characterization showed that A1 PrLD mutations and transporting A1 backin the M9 to sequence the nucleus induce its [25 mislocalization,45,46]. This by prohibiting data is corroborated Transportin 1 (TNPO1) by studies from in other neurodegenerativeproperly disorders binding to (e.g., the M9 amyotrophic region and transpor lateralting A1 sclerosis back to the (ALS),nucleus [25,45,46]. frontotemporal This lobar degeneration, anddata Alzheimer is corroborated0s by and studies Huntington in other neurodegenerative0s diseases), disorders showing (e.g., thatamyotrophic mutations lateral sclerosis (ALS), frontotemporal lobar degeneration, and Alzheimer′s and Hunting- within the PrLD of RBPston′s alterdiseases), protein-protein showing that mutations interactions, within the PrLD leading of RBPs toalter mislocalization protein-protein in- and aggregate formation thatteractions, influence leading cellularto mislocalization processes and aggregate [47–50 formation]. that influence cellular pro- cesses [47–50]. Figure 1. MS-associated A1 mutations F281L and P275S are mislocalized to the cytoplasm. Immunofluorescence of non- Figurestimulated, 1. MS-associated HEK293Tcells expressing A1 mutations optogenetic F281Lfusion proteins and P275Sof (A) full-length, are mislocalized wild-type A1 to(OptoA1WT), the cytoplasm. (B) Im- munofluorescenceA1(F281L) (OptoA1(F281L)), of non-stimulated, (C) A1(P275S) (OptoA1(P275S)) HEK293Tcells and ( expressingD) Opto-mCh 12 optogenetic h post-transfection. fusion The proteinscytoplasm is of (A) full- delineated by staining for G3BP1 (green), while nuclei are outlined (white outlines) using DAPI staining in merged images. length,Scale wild-type bars = 5 µm. ( A1E) Cytoplasmic/nuclear (OptoA1WT), fluorescence (B) A1(F281L) intensity (OptoA1(F281L)),ratio analysis of OptoA1 fusion (C) A1(P275S) proteins and Opto-mCh. (OptoA1(P275S))
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