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Article: Conserved gene signatures shared among

Minaya, Miguel A / Mahali, Sidhartha / Iyer, Abhirami K / Eteleeb, Abdallah M / Martinez, Rita / Huang, Guangming / Budde, John / Temple, Sally / Nana, Alissa L / Seeley, William W / Spina, Salvatore / Grinberg, Lea T / Harari, Oscar / Karch, Celeste M

Frontiers in molecular biosciences

2023 Volume 10, Page(s) 1051494

Abstract: Introduction: ...

Abstract	Introduction:
Language	English
Publishing date	2023-02-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2814330-9
ISSN	2296-889X
ISSN	2296-889X
DOI	10.3389/fmolb.2023.1051494
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Article ; Online: Cellular Sources and Neuroprotective Roles of Interleukin-10 in the Facial Motor Nucleus after Axotomy.

Runge, Elizabeth M / Setter, Deborah O / Iyer, Abhirami K / Regele, Eric J / Kennedy, Felicia M / Sanders, Virginia M / Jones, Kathryn J

Cells

2022 Volume 11, Issue 19

Abstract: Facial motoneuron (FMN) survival is mediated by CD4+ T cells in an interleukin-10 (IL-10)-dependent manner after facial nerve axotomy (FNA), but CD4+ T cells themselves are not the source of this neuroprotective IL-10. The aims of this study were to (1) ... ...

Abstract	Facial motoneuron (FMN) survival is mediated by CD4+ T cells in an interleukin-10 (IL-10)-dependent manner after facial nerve axotomy (FNA), but CD4+ T cells themselves are not the source of this neuroprotective IL-10. The aims of this study were to (1) identify the temporal and cell-specific induction of IL-10 expression in the facial motor nucleus and (2) elucidate the neuroprotective capacity of this expression after axotomy. Immunohistochemistry revealed that FMN constitutively produced IL-10, whereas astrocytes were induced to make IL-10 after FNA.
MeSH term(s)	Animals ; Axotomy ; Facial Nerve Injuries/genetics ; Facial Nerve Injuries/metabolism ; Facial Nucleus/metabolism ; Flavin Mononucleotide/metabolism ; Interleukin-10/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Motor Neurons/metabolism ; Neuroprotection ; RNA, Messenger/metabolism
Chemical Substances	RNA, Messenger ; Interleukin-10 (130068-27-8) ; Flavin Mononucleotide (7N464URE7E)
Language	English
Publishing date	2022-10-09
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11193167
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Article ; Online: Targeted ASO-mediated Atp1a2 knockdown in astrocytes reduces SOD1 aggregation and accelerates disease onset in mutant SOD1 mice.

Iyer, Abhirami K / Schoch, Kathleen M / Verbeck, Anthony / Galasso, Grant / Chen, Hao / Smith, Sarah / Oldenborg, Anna / Miller, Timothy M / Karch, Celeste M / Bonni, Azad

PloS one

2023 Volume 18, Issue 11, Page(s) e0294731

Abstract: Astrocyte-specific ion pump α2-Na+/K+-ATPase plays a critical role in the pathogenesis ... to induce α2-Na+/K+-ATPase knockdown in the widely used ALS animal model, SOD1*G93A mice. Two ASOs led ... these results reveal a role for α2-Na+/K+-ATPase in SOD1 aggregation and highlight the critical effect ...

Abstract	Astrocyte-specific ion pump α2-Na+/K+-ATPase plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Here, we test the effect of Atp1a2 mRNA-specific antisense oligonucleotides (ASOs) to induce α2-Na+/K+-ATPase knockdown in the widely used ALS animal model, SOD1*G93A mice. Two ASOs led to efficient Atp1a2 knockdown and significantly reduced SOD1 aggregation in vivo. Although Atp1a2 ASO-treated mice displayed no off-target or systemic toxicity, the ASO-treated mice exhibited an accelerated disease onset and shorter lifespan than control mice. Transcriptomics studies reveal downregulation of genes involved in oxidative response, metabolic pathways, trans-synaptic signaling, and upregulation of genes involved in glutamate receptor signaling and complement activation, suggesting a potential role for these molecular pathways in de-coupling SOD1 aggregation from survival in Atp1a2 ASO-treated mice. Together, these results reveal a role for α2-Na+/K+-ATPase in SOD1 aggregation and highlight the critical effect of temporal modulation of genetically validated therapeutic targets in neurodegenerative diseases.
MeSH term(s)	Animals ; Mice ; Amyotrophic Lateral Sclerosis/pathology ; Astrocytes/metabolism ; Disease Models, Animal ; Mice, Transgenic ; Motor Neurons/metabolism ; Sodium-Potassium-Exchanging ATPase/metabolism ; Spinal Cord/metabolism ; Superoxide Dismutase/metabolism ; Superoxide Dismutase-1/genetics ; Superoxide Dismutase-1/metabolism
Chemical Substances	Atp1a2 protein, mouse (EC 3.6.1.-) ; Sodium-Potassium-Exchanging ATPase (EC 7.2.2.13) ; Superoxide Dismutase (EC 1.15.1.1) ; Superoxide Dismutase-1 (EC 1.15.1.1) ; Sod1 protein, mouse (EC 1.15.1.1)
Language	English
Publishing date	2023-11-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0294731
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Article ; Online: Targeted ASO-mediated Atp1a2 knockdown in astrocytes reduces SOD1 aggregation and accelerates disease onset in mutant SOD1 mice.

Abhirami K Iyer / Kathleen M Schoch / Anthony Verbeck / Grant Galasso / Hao Chen / Sarah Smith / Anna Oldenborg / Timothy M Miller / Celeste M Karch / Azad Bonni

PLoS ONE, Vol 18, Iss 11, p e

2023 Volume 0294731

Abstract	Astrocyte-specific ion pump α2-Na+/K+-ATPase plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Here, we test the effect of Atp1a2 mRNA-specific antisense oligonucleotides (ASOs) to induce α2-Na+/K+-ATPase knockdown in the widely used ALS animal model, SOD1*G93A mice. Two ASOs led to efficient Atp1a2 knockdown and significantly reduced SOD1 aggregation in vivo. Although Atp1a2 ASO-treated mice displayed no off-target or systemic toxicity, the ASO-treated mice exhibited an accelerated disease onset and shorter lifespan than control mice. Transcriptomics studies reveal downregulation of genes involved in oxidative response, metabolic pathways, trans-synaptic signaling, and upregulation of genes involved in glutamate receptor signaling and complement activation, suggesting a potential role for these molecular pathways in de-coupling SOD1 aggregation from survival in Atp1a2 ASO-treated mice. Together, these results reveal a role for α2-Na+/K+-ATPase in SOD1 aggregation and highlight the critical effect of temporal modulation of genetically validated therapeutic targets in neurodegenerative diseases.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: MS4A4A modifies the risk of Alzheimer disease by regulating lipid metabolism and immune response in a unique microglia state.

medRxiv : the preprint server for health sciences

2023

Abstract: Genome-wide association studies (GWAS) have identified many modifiers of Alzheimer disease (AD) risk enriched in microglia. Two of these modifiers are common variants in ... ...

Abstract	Genome-wide association studies (GWAS) have identified many modifiers of Alzheimer disease (AD) risk enriched in microglia. Two of these modifiers are common variants in the
Language	English
Publishing date	2023-02-08
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.02.06.23285545
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Article ; Online: Temporospatial Analysis and New Players in the Immunology of Amyotrophic Lateral Sclerosis.

Iyer, Abhirami K / Jones, Kathryn J / Sanders, Virginia M / Walker, Chandler L

International journal of molecular sciences

2018 Volume 19, Issue 2

Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of lower and upper motor neurons (MN) leading to muscle weakness, paralysis and eventually death. Although a highly varied etiology results in ALS, it ... ...

Abstract	Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of lower and upper motor neurons (MN) leading to muscle weakness, paralysis and eventually death. Although a highly varied etiology results in ALS, it broadly manifests itself as sporadic and familial forms that have evident similarities in clinical symptoms and disease progression. There is a tremendous amount of knowledge on molecular mechanisms leading to loss of MNs and neuromuscular junctions (NMJ) as major determinants of disease onset, severity and progression in ALS. Specifically, two main opposing hypotheses, the dying forward and dying back phenomena, exist to account for NMJ denervation. The former hypothesis proposes that the earliest degeneration occurs at the central MNs and proceeds to the NMJ, whereas in the latter, the peripheral NMJ is the site of precipitating degeneration progressing backwards to the MN cell body. A large body of literature strongly indicates a role for the immune system in disease onset and progression via regulatory involvement at the level of both the central and peripheral nervous systems (CNS and PNS). In this review, we discuss the earliest reported immune responses with an emphasis on newly identified immune players in mutant superoxide dismutase 1 (mSOD1) transgenic mice, the gold standard mouse model for ALS.
MeSH term(s)	Amyotrophic Lateral Sclerosis/immunology ; Animals ; Humans ; Muscle, Skeletal/immunology ; Muscle, Skeletal/pathology ; Neuromuscular Junction/immunology ; Neuromuscular Junction/pathology ; Schwann Cells/immunology ; Schwann Cells/pathology ; Spatio-Temporal Analysis
Language	English
Publishing date	2018-02-23
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms19020631
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Article ; Online: Conserved gene signatures shared among MAPT mutations reveal defects in calcium signaling

Miguel A. Minaya / Sidhartha Mahali / Abhirami K. Iyer / Abdallah M. Eteleeb / Rita Martinez / Guangming Huang / John Budde / Sally Temple / Alissa L. Nana / William W. Seeley / Salvatore Spina / Lea T. Grinberg / Oscar Harari / Celeste M. Karch

Frontiers in Molecular Biosciences, Vol

2023 Volume 10

Abstract: Introduction: More than 50 mutations in the MAPT gene result in heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD-Tau). However, early pathogenic events that lead to disease and the degree to which they are common across MAPT ...

Abstract	Introduction: More than 50 mutations in the MAPT gene result in heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD-Tau). However, early pathogenic events that lead to disease and the degree to which they are common across MAPT mutations remain poorly understood. The goal of this study is to determine whether there is a common molecular signature of FTLD-Tau.Methods: We analyzed genes differentially expressed in induced pluripotent stem cell–derived neurons (iPSC-neurons) that represent the three major categories of MAPT mutations: splicing (IVS10 + 16), exon 10 (p.P301L), and C-terminal (p.R406W) compared with isogenic controls. The genes that were commonly differentially expressed in MAPT IVS10 + 16, p.P301L, and p.R406W neurons were enriched in trans-synaptic signaling, neuronal processes, and lysosomal function. Many of these pathways are sensitive to disruptions in calcium homeostasis. One gene, CALB1, was significantly reduced across the three MAPT mutant iPSC-neurons and in a mouse model of tau accumulation. We observed a significant reduction in calcium levels in MAPT mutant neurons compared with isogenic controls, pointing to a functional consequence of this disrupted gene expression. Finally, a subset of genes commonly differentially expressed across MAPT mutations were also dysregulated in brains from MAPT mutation carriers and to a lesser extent in brains from sporadic Alzheimer disease and progressive supranuclear palsy, suggesting that molecular signatures relevant to genetic and sporadic forms of tauopathy are captured in a dish. The results from this study demonstrate that iPSC-neurons capture molecular processes that occur in human brains and can be used to pinpoint common molecular pathways involving synaptic and lysosomal function and neuronal development, which may be regulated by disruptions in calcium homeostasis.
Keywords	IPSC-derived neurons ; frontotemporal dementia (FTD) ; MAPT mutations (tau) ; transcriptomics ; calcium signaling ; Biology (General) ; QH301-705.5
Subject code	572 ; 571
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: CD4+ T cell expression of the IL-10 receptor is necessary for facial motoneuron survival after axotomy.

Runge, Elizabeth M / Iyer, Abhirami K / Setter, Deborah O / Kennedy, Felicia M / Sanders, Virginia M / Jones, Kathryn J

Journal of neuroinflammation

2020 Volume 17, Issue 1, Page(s) 121

Abstract: Background: After peripheral nerve transection, facial motoneuron (FMN) survival depends on an intact CD4+ T cell population and a central source of interleukin-10 (IL-10). However, it has not been determined previously whether CD4+ T cells participate ... ...

Abstract	Background: After peripheral nerve transection, facial motoneuron (FMN) survival depends on an intact CD4+ T cell population and a central source of interleukin-10 (IL-10). However, it has not been determined previously whether CD4+ T cells participate in the central neuroprotective IL-10 cascade after facial nerve axotomy (FNA). Methods: Immunohistochemical labeling of CD4+ T cells, pontine vasculature, and central microglia was used to determine whether CD4+ T cells cross the blood-brain barrier and enter the facial motor nucleus (FMNuc) after FNA. The importance of IL-10 signaling in CD4+ T cells was assessed by performing adoptive transfer of IL-10 receptor beta (IL-10RB)-deficient CD4+ T cells into immunodeficient mice prior to injury. Histology and qPCR were utilized to determine the impact of IL-10RB-deficient T cells on FMN survival and central gene expression after FNA. Flow cytometry was used to determine whether IL-10 signaling in T cells was necessary for their differentiation into neuroprotective subsets. Results: CD4+ T cells were capable of crossing the blood-brain barrier and associating with reactive microglial nodules in the axotomized FMNuc. Full induction of central IL-10R gene expression after FNA was dependent on CD4+ T cells, regardless of their own IL-10R signaling capability. Surprisingly, CD4+ T cells lacking IL-10RB were incapable of mediating neuroprotection after axotomy and promoted increased central expression of genes associated with microglial activation, antigen presentation, T cell co-stimulation, and complement deposition. There was reduced differentiation of IL-10RB-deficient CD4+ T cells into regulatory CD4+ T cells in vitro. Conclusions: These findings support the interdependence of IL-10- and CD4+ T cell-mediated mechanisms of neuroprotection after axotomy. CD4+ T cells may potentiate central responsiveness to IL-10, while IL-10 signaling within CD4+ T cells is necessary for their ability to rescue axotomized motoneuron survival. We propose that loss of IL-10 signaling in CD4+ T cells promotes non-neuroprotective autoimmunity after FNA.
MeSH term(s)	Animals ; Axotomy/methods ; CD4-Positive T-Lymphocytes/metabolism ; Cell Survival/physiology ; Cells, Cultured ; Facial Nerve/metabolism ; Facial Nerve Injuries/genetics ; Facial Nerve Injuries/metabolism ; Female ; Gene Expression ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Motor Neurons/metabolism ; Receptors, Interleukin-10/biosynthesis ; Receptors, Interleukin-10/genetics
Chemical Substances	Receptors, Interleukin-10
Language	English
Publishing date	2020-04-17
Publishing country	England
Document type	Journal Article
ISSN	1742-2094
ISSN (online)	1742-2094
DOI	10.1186/s12974-020-01772-x
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Article ; Online: Temporospatial Analysis and New Players in the Immunology of Amyotrophic Lateral Sclerosis

Abhirami K. Iyer / Kathryn J. Jones / Virginia M. Sanders / Chandler L. Walker

International Journal of Molecular Sciences, Vol 19, Iss 2, p

2018 Volume 631

Abstract	Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of lower and upper motor neurons (MN) leading to muscle weakness, paralysis and eventually death. Although a highly varied etiology results in ALS, it broadly manifests itself as sporadic and familial forms that have evident similarities in clinical symptoms and disease progression. There is a tremendous amount of knowledge on molecular mechanisms leading to loss of MNs and neuromuscular junctions (NMJ) as major determinants of disease onset, severity and progression in ALS. Specifically, two main opposing hypotheses, the dying forward and dying back phenomena, exist to account for NMJ denervation. The former hypothesis proposes that the earliest degeneration occurs at the central MNs and proceeds to the NMJ, whereas in the latter, the peripheral NMJ is the site of precipitating degeneration progressing backwards to the MN cell body. A large body of literature strongly indicates a role for the immune system in disease onset and progression via regulatory involvement at the level of both the central and peripheral nervous systems (CNS and PNS). In this review, we discuss the earliest reported immune responses with an emphasis on newly identified immune players in mutant superoxide dismutase 1 (mSOD1) transgenic mice, the gold standard mouse model for ALS.
Keywords	amyotrophic lateral sclerosis (ALS) ; immune response ; neuroimmunology ; motor neuron disease ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2018-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation.

Acta neuropathologica

2023 Volume 145, Issue 6, Page(s) 749–772

Abstract: TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer's disease and frontotemporal dementia, while homozygous TREM2 mutations cause a rare ... ...

Abstract	TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer's disease and frontotemporal dementia, while homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two NHD families: three homozygous TREM2 p.Q33X mutation carriers (termed NHD), two heterozygous mutation carriers, one related non-carrier, and two unrelated non-carriers. Transcriptomic and biochemical analyses revealed that iMGLs from NHD patients exhibited lysosomal dysfunction, downregulation of cholesterol genes, and reduced lipid droplets compared to controls. Also, NHD iMGLs displayed defective activation and HLA antigen presentation. This defective activation and lipid droplet content were restored by enhancing lysosomal biogenesis through mTOR-dependent and independent pathways. Alteration in lysosomal gene expression, such as decreased expression of genes implicated in lysosomal acidification (ATP6AP2) and chaperone mediated autophagy (LAMP2), together with reduction in lipid droplets were also observed in post-mortem brain tissues from NHD patients, thus closely recapitulating in vivo the phenotype observed in iMGLs in vitro. Our study provides the first cellular and molecular evidence that the TREM2 p.Q33X mutation in microglia leads to defects in lysosomal function and that compounds targeting lysosomal biogenesis restore a number of NHD microglial defects. A better understanding of how microglial lipid metabolism and lysosomal machinery are altered in NHD and how these defects impact microglia activation may provide new insights into mechanisms underlying NHD and other neurodegenerative diseases.
MeSH term(s)	Adult ; Humans ; Microglia/metabolism ; Lipid Metabolism/genetics ; Loss of Function Mutation ; Mutation/genetics ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Lysosomes/metabolism ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/metabolism ; Receptors, Immunologic/genetics ; Receptors, Immunologic/metabolism ; Prorenin Receptor
Chemical Substances	TREM2 protein, human ; Membrane Glycoproteins ; Receptors, Immunologic ; ATP6AP2 protein, human ; Prorenin Receptor
Language	English
Publishing date	2023-04-28
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-023-02568-y
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