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Mitigation of ALS Pathology by Neuron-Specific Inhibition of Nuclear Factor Kappa B Signaling Research Report: Regular Manuscript Mitigation of ALS pathology by neuron-specific inhibition of nuclear factor kappa B signaling https://doi.org/10.1523/JNEUROSCI.0536-20.2020 Cite as: J. Neurosci 2020; 10.1523/JNEUROSCI.0536-20.2020 Received: 6 March 2020 Revised: 12 May 2020 Accepted: 18 May 2020 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2020 Dutta et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. 1 Mitigation of ALS pathology by neuron-specific inhibition of nuclear factor kappa B 2 signaling 3 4 Kallol Dutta1, Sai Sampath Thammisetty1, Hejer Boutej1, Christine Bareil1 and Jean-Pierre 5 Julien1, 2. 6 7 1 CERVO Brain Research Centre, Québec, Québec, Canada; 2 Department of Psychiatry and 8 Neuroscience, Université Laval, Québec City, Québec, Canada. 9 10 Address for correspondence: 11 Jean-Pierre Julien, CERVO Brain Research Centre; 2601, de la Canardière, Québec city, 12 (Québec), G1J2G3, CANADA. Tel: 418 663-5000 ext 4785 13 E-mail:[email protected] 14 15 Abbreviated title: Mitigation of ALS by neuronal inhibition of NF-kappaB 16 17 xNumber of pages:38 18 xNumber of figures- 11;tables- 1 19 xNumber of words for Abstract-155;Introduction- 611; Discussion-1171 20 xConflict of interest statement: The authors declare no competing financial interests. 21 xAcknowledgments: K.D. would like to thank Geneviève Soucy for her technical assistance; 22 Drs. Silvia Pozzi, Prakash K. Mishra and Karine Plourde for their critical comments and 23 discussions; animal facility technicians for care of the transgenic mice. This work was funded by 24 grants from the Canadian Institutes of Health Research, ALS Society of Canada and Brain 25 Canada. J.-P.J. holds a Canada Research Chair Tier 1 on mechanisms of neurodegeneration. 26 27 28 29 30 31 1 32 Abstract 33 To investigate the role of neuronal NF-κB activity in pathogenesis of amyotrophic lateral 34 sclerosis (ALS), we generated transgenic mice with neuron-specific expression of a super- 35 repressor form of the NF-κB inhibitor (IκBα-SR) which were then crossed with mice of both 36 sexes, expressing ALS-linked gene mutants for TAR DNA-binding protein (TDP-43) and 37 superoxide dismutase 1 (SOD1). Remarkably, neuronal expression of IκBα-SRtransgene in mice 38 expressing TDP-43A315T or TDP-43G348C miceled to a decrease in cytoplasmic to nuclear ratio of 39 human TDP-43. The mitigation of TDP-43 neuropathology by IκBα-SR, which is likely due toan 40 induction of autophagy, was associated with amelioration of cognitive and motor deficits as well 41 as reduction of motor neuron loss and gliosis. Neuronal suppression of NF-κB activity in 42 SOD1G93A mice also resulted in neuroprotection with reduction of misfolded SOD1 levels and 43 significant extension of lifespan. The results suggest that neuronal NF-κB signaling constitutes a 44 novel therapeutic target for ALS diseaseand related disorders with TDP-43 proteinopathy. 45 46 47 Significance statement 48 This study reports that neuron-specific expression of I-kappa B super-repressor mitigated 49 behavioral and pathological changes in transgenic mouse models of ALS expressing mutant 50 forms of either Tar DNA binding protein 43 (TDP-43) or superoxide dismutase. The results 51 suggest that neuronal NF-κB signaling constitutes a novel therapeutic target for ALS and related 52 disorders with TDP-43 proteinopathy. 53 54 55 56 57 58 59 60 61 62 2 63 Introduction 64 65 Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of upper and lower 66 motor neurons. ALS evolves with paralysis and the disease is generally fatal within 2 to 5 years 67 after the onset of symptoms. Familial ALS, accounting for around 10% of the ALS cases, is 68 caused by mutations in various genes. Expanded hexanucleotide repeats in C9orf72 account for 69 almost 40% of the familial cases whereas other mutated genes include superoxide dismutase 1 70 (SOD1), TAR DNA-binding protein (TARDBP) encoding TDP-43, fused in sarcoma (FUS) and 71 ubiquilin-2 (UBQLN2)(Picher-Martel et al., 2015). Abnormal cytoplasmic accumulations of 72 TDP-43 are a common occurrence in degenerating neurons of the central nervous system (CNS) 73 in the majority of ALS cases and of tau-negative frontotemporal dementia (FTD) as well as in 74 subsets of Alzheimer’s disease and Parkinson’s disease(Scotter et al., 2015). 75 76 Unexpectedly, TDP-43 was found to directly interact with the p65 subunit of nuclear factor 77 kappa B (NF-κB) in CNS samples from ALS individuals (Swarup et al., 2011b) and also from 78 cases with mild cognitive impairment with episodic memory deficits(Ohta et al., 2014). 79 Furthermore, we reported that TDP-43 can serve as co-activator of NF-κB in cultured 80 cells(Swarup et al., 2011b). An involvement of NF-κB in ALS is further supported by the 81 evidence that pharmacological inhibition of this pathway conferred beneficial effects in mouse 82 models of ALS including attenuation of TDP-43 pathology in motor neurons (Swarup et al., 83 2011b; Dutta et al., 2017). However, since drug inhibitors NF-κB activity can target systemically 84 different cell types it has remained unknown whether deregulated NF-κB signaling within 85 neuronal cells contributes to disease pathology and especially formation of abnormal protein 86 aggregates. 87 88 NF-κB is a ubiquitously expressed, protean eukaryotic transcription factor that is involved in a 89 multitude of physiological functions. NF-κB acts as transcription activator for several genes 90 associated with inflammation and it is considered as one of the key modulators for inflammatory 91 pathways. NF-κB remains sequestered in cellular cytosol as a complex composed of either of 92 two classes of proteins, class 1 containing of NF-κB1 (p50/p105) and NF-κB2 (p52/p100), and 93 class 2 containing RelA (p65), RelB and c-Rel. At basal state, NF-κB proteins are trapped in cell 3 94 cytoplasm by association with inhibitory (I) κB proteins including IκBα, IκBβ, IκBε and Bcl-3 95 (Ghosh and Karin, 2002), their activation being dependent on a series of sequentially activated 96 kinases. When classically activated, a kinase complex (IκB-kinase or IKK complex) 97 phosphorylates IκBα on Ser32 and Ser36, leading to its ubiquitination and proteasomal 98 degradation(Viatour et al., 2005). As a result, NF-κB is released and translocates into the 99 nucleus to mediate its functions. NF-κB can undergo post-translational modifications such as 100 phosphorylation or acetylation prior to nuclear translocation. 101 102 To investigate the role of neuronal NF-κB signaling in ALS pathogenesis, we 103 generatedtransgenic mice with neuron-specific expression of a super-repressor form of the NF- 104 κB inhibitor IkappaB(IκBαS32A, S36A). The IκBα super-repressor mice were further cross-bred 105 with three different transgenic mouse models of ALS, two transgenic lines expressing human 106 TDP-43 with point mutations A315T and G348C and a mouse model expressed SOD1 with 107 G93A mutation. The hTDP-43A315T and hTDP-43G348C transgenic mice exhibit during aging 108 abnormal cytoplasmic accumulations of human TDP-43, substantial motor neuron loss as well as 109 motor and cognitive deficits (Swarup et al., 2011a). On the other hand, the well-established 110 SOD1G93Amice replicate ALS disease phenotypeswith accumulations of misfolded SOD1 111 species, severe motor neuron loss resulting in short lifespan (Dutta et al., 2018). Here, we report 112 that neuron-specific expression ofIκB-SR ameliorated behavioral and pathological phenotypes in 113 three mouse models of ALS carrying either human mutated TDP-43 or SOD1 transgenes. The 114 results suggest that neuronal NF-κB signaling constitutes a novel therapeutic target for ALS 115 disease. 116 117 Materials and Methods 118 119 DNA constructs, generation of transgenic mice and genotyping 120 121 The DNA of neurofilament H (NFH) promoter was amplified by PCR using the genomic DNA 122 purified from mouse tail. The following primers were used for the NFH amplification: 5' primer: 123 5'-GGGACGACGGTACCCTAGGACATTCTGGGCTGAGATC-3' and 3' primer: 5'- 124 GGGACGACGTCGACCAGCGGAGCGGGAGTGCGGGGCT-3'. A 2.8 Kb fragment was 4 125 purified on agarose gel and subcloned into KpnI-SalI restriction sites of pBluescript KS+ 126 (pBSKS-NFH promoter). Flag-EGFP fragment was obtained by PCR using pEGFP-N3 plasmid 127 as template (CLONTECH). The following primers were used for the Flag-EGFP fragment 128 amplification: 5' primer: 5'-GGGACGACCTGCAGGAGGCAGCATGGACTA 129 CAAAGACGACGACGACAAGGTGAGCAAGGGCGAGGA-3' and 3' primer: 3'-GGGACGA 130 CGGATCCCTTGTACAGCTCGTCCATGC-3'. The obtained fragment was introduced into 131 corresponding restriction sites of pBSKS-NFH promoter plasmid. The human IκBα (SS32, 132 36AA) cDNA was amplified by PCR using the plasmid PCMV4-3HA/ IκBα (SS32, 36AA) 133 (Addgene plasmid # 24143) (Sun et al., 1996) as template. The following primers were used for 134 the PCR amplification: 135 5' primer: 5'-GGGACGACGGATCCTTCCAGGCGGCCGAGCGCCCCCAGG-3' and 136 3' primer: 5’-GGGACGACGCGGCCGCTCATAACGTCAGACGCTGGCCTCCA-3'. 137 A 953 bpBamHI /NotI fragment corresponding to the human IκBα (SS32, 36AA) cDNA was 138 introduced into pBSKS recombinant vector. The integrity of the final construct was verified by 139 sequencing. 140 For the generation of the transgenic mice, a BssHII-BssHII DNA fragment of 4.9 Kb was 141 isolated on agarose gel for microinjection.
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