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Article ; Online: Nuclear pores: the gate to neurodegeneration.

Li, Nan / Lagier-Tourenne, Clotilde

2018 Volume 21, Issue 2, Page(s) 156–158

MeSH term(s)	Active Transport, Cell Nucleus ; Amyotrophic Lateral Sclerosis ; DNA-Binding Proteins ; Nuclear Envelope ; Nuclear Pore ; Humans
Chemical Substances	DNA-Binding Proteins
Language	English
Publishing date	2018-01-05
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	1420596-8
ISSN	1546-1726 ; 1097-6256
ISSN (online)	1546-1726
ISSN	1097-6256
DOI	10.1038/s41593-017-0066-0
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Zs.A 4891: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 67: Show issues

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Article ; Online: Neuronal STING activation in amyotrophic lateral sclerosis and frontotemporal dementia.

Marques, Christine / Held, Aaron / Dorfman, Katherine / Sung, Joon / Song, Catherine / Kavuturu, Amey S / Aguilar, Corey / Russo, Tommaso / Oakley, Derek H / Albers, Mark W / Hyman, Bradley T / Petrucelli, Leonard / Lagier-Tourenne, Clotilde / Wainger, Brian J

Acta neuropathologica

2024 Volume 147, Issue 1, Page(s) 56

Abstract: The stimulator of interferon genes (STING) pathway has been implicated in neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis (ALS). While prior studies have focused on STING within immune cells, little is known ... ...

Abstract	The stimulator of interferon genes (STING) pathway has been implicated in neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis (ALS). While prior studies have focused on STING within immune cells, little is known about STING within neurons. Here, we document neuronal activation of the STING pathway in human postmortem cortical and spinal motor neurons from individuals affected by familial or sporadic ALS. This process takes place selectively in the most vulnerable cortical and spinal motor neurons but not in neurons that are less affected by the disease. Concordant STING activation in layer V cortical motor neurons occurs in a mouse model of C9orf72 repeat-associated ALS and frontotemporal dementia (FTD). To establish that STING activation occurs in a neuron-autonomous manner, we demonstrate the integrity of the STING signaling pathway, including both upstream activators and downstream innate immune response effectors, in dissociated mouse cortical neurons and neurons derived from control human induced pluripotent stem cells (iPSCs). Human iPSC-derived neurons harboring different familial ALS-causing mutations exhibit increased STING signaling with DNA damage as a main driver. The elevated downstream inflammatory markers present in ALS iPSC-derived neurons can be suppressed with a STING inhibitor. Our results reveal an immunophenotype that consists of innate immune signaling driven by the STING pathway and occurs specifically within vulnerable neurons in ALS/FTD.
MeSH term(s)	Animals ; Humans ; Mice ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; C9orf72 Protein/genetics ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/metabolism ; Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism ; Pick Disease of the Brain
Chemical Substances	C9orf72 Protein ; STING1 protein, human
Language	English
Publishing date	2024-03-13
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-024-02688-z
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Article ; Online: Taking on the Elephant in the Tissue Culture Room: iPSC Modeling for Sporadic ALS.

Wainger, Brian J / Lagier-Tourenne, Clotilde

Cell stem cell

2018 Volume 23, Issue 4, Page(s) 466–467

Abstract: Modeling ALS remains a major challenge since the vast majority of cases are sporadic. Recently in Nature Medicine, Fujimori et al. leverage genetic heterogeneity and define subgroups of iPSC-derived motor neurons using multiplex phenotypic profiles, and ... ...

Abstract	Modeling ALS remains a major challenge since the vast majority of cases are sporadic. Recently in Nature Medicine, Fujimori et al. leverage genetic heterogeneity and define subgroups of iPSC-derived motor neurons using multiplex phenotypic profiles, and thus make substantial progress toward robust modeling of both familial and sporadic ALS.
MeSH term(s)	Amyotrophic Lateral Sclerosis ; Humans ; Induced Pluripotent Stem Cells ; Motor Neurons
Language	English
Publishing date	2018-11-08
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2375354-7
ISSN	1875-9777 ; 1934-5909
ISSN (online)	1875-9777
ISSN	1934-5909
DOI	10.1016/j.stem.2018.09.015
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Zs.A 6589: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Animal models of neurodegenerative diseases.

Dawson, Ted M / Golde, Todd E / Lagier-Tourenne, Clotilde

Nature neuroscience

2018 Volume 21, Issue 10, Page(s) 1370–1379

Abstract: Animal models of adult-onset neurodegenerative diseases have enhanced the understanding of the molecular pathogenesis of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Nevertheless, our understanding ...

Abstract	Animal models of adult-onset neurodegenerative diseases have enhanced the understanding of the molecular pathogenesis of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Nevertheless, our understanding of these disorders and the development of mechanistically designed therapeutics can still benefit from more rigorous use of the models and from generation of animals that more faithfully recapitulate human disease. Here we review the current state of rodent models for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. We discuss the limitations and utility of current models, issues regarding translatability, and future directions for developing animal models of these human disorders.
MeSH term(s)	Animals ; Disease Models, Animal ; Humans ; Neurodegenerative Diseases
Language	English
Publishing date	2018-09-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1420596-8
ISSN	1546-1726 ; 1097-6256
ISSN (online)	1546-1726
ISSN	1097-6256
DOI	10.1038/s41593-018-0236-8
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Article ; Online: Disruption of RNA Metabolism in Neurological Diseases and Emerging Therapeutic Interventions.

Nussbacher, Julia K / Tabet, Ricardos / Yeo, Gene W / Lagier-Tourenne, Clotilde

Neuron

2019 Volume 102, Issue 2, Page(s) 294–320

Abstract: RNA binding proteins are critical to the maintenance of the transcriptome via controlled regulation of RNA processing and transport. Alterations of these proteins impact multiple steps of the RNA life cycle resulting in various molecular phenotypes such ... ...

Abstract	RNA binding proteins are critical to the maintenance of the transcriptome via controlled regulation of RNA processing and transport. Alterations of these proteins impact multiple steps of the RNA life cycle resulting in various molecular phenotypes such as aberrant RNA splicing, transport, and stability. Disruption of RNA binding proteins and widespread RNA processing defects are increasingly recognized as critical determinants of neurological diseases. Here, we describe distinct mechanisms by which the homeostasis of RNA binding proteins is compromised in neurological disorders through their reduced expression level, increased propensity to aggregate or sequestration by abnormal RNAs. These mechanisms all converge toward altered neuronal function highlighting the susceptibility of neurons to deleterious changes in RNA expression and the central role of RNA binding proteins in preserving neuronal integrity. Emerging therapeutic approaches to mitigate or reverse alterations of RNA binding proteins in neurological diseases are discussed.
MeSH term(s)	Animals ; Autophagy ; CRISPR-Cas Systems ; Genetic Therapy ; Genetic Vectors ; Homeostasis ; Humans ; Molecular Targeted Therapy ; Nervous System Diseases/genetics ; Nervous System Diseases/metabolism ; Nervous System Diseases/therapy ; Oligoribonucleotides, Antisense/therapeutic use ; Paraneoplastic Syndromes, Nervous System/genetics ; Paraneoplastic Syndromes, Nervous System/metabolism ; Paraneoplastic Syndromes, Nervous System/therapy ; RNA/metabolism ; RNA Processing, Post-Transcriptional ; RNA Splicing ; RNA Stability ; RNA Transport ; RNA-Binding Proteins/metabolism
Chemical Substances	Oligoribonucleotides, Antisense ; RNA-Binding Proteins ; RNA (63231-63-0)
Language	English
Publishing date	2019-04-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2019.03.014
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Zs.A 2496: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: iPSC motor neurons, but not other derived cell types, capture gene expression changes in postmortem sporadic ALS motor neurons.

Held, Aaron / Adler, Michelle / Marques, Christine / Reyes, Charles Jourdan / Kavuturu, Amey S / Quadros, Ana R A A / Ndayambaje, I Sandra / Lara, Erika / Ward, Michael / Lagier-Tourenne, Clotilde / Wainger, Brian J

Cell reports

2023 Volume 42, Issue 9, Page(s) 113046

Abstract: Motor neuron degeneration, the defining feature of amyotrophic lateral sclerosis (ALS), is a primary example of cell-type specificity in neurodegenerative diseases. Using isogenic pairs of induced pluripotent stem cells (iPSCs) harboring different ... ...

Abstract	Motor neuron degeneration, the defining feature of amyotrophic lateral sclerosis (ALS), is a primary example of cell-type specificity in neurodegenerative diseases. Using isogenic pairs of induced pluripotent stem cells (iPSCs) harboring different familial ALS mutations, we assess the capacity of iPSC-derived lower motor neurons, sensory neurons, astrocytes, and superficial cortical neurons to capture disease features including transcriptional and splicing dysregulation observed in human postmortem neurons. At early time points, differentially regulated genes in iPSC-derived lower motor neurons, but not other cell types, overlap with one-third of the differentially regulated genes in laser-dissected motor neurons from ALS compared with control postmortem spinal cords. For genes altered in both the iPSC model and bona fide human lower motor neurons, expression changes correlate between the two populations. In iPSC-derived lower motor neurons, but not other derived cell types, we detect the downregulation of genes affected by TDP-43-dependent splicing. This reduction takes place exclusively within genotypes known to involve TDP-43 pathology.
MeSH term(s)	Humans ; Amyotrophic Lateral Sclerosis/pathology ; Induced Pluripotent Stem Cells/metabolism ; Motor Neurons/metabolism ; Gene Expression ; DNA-Binding Proteins/metabolism
Chemical Substances	DNA-Binding Proteins
Language	English
Publishing date	2023-08-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.113046
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Article ; Online: Interactions between FUS and the C-terminal Domain of Nup62 are Sufficient for their Co-phase Separation into Amorphous Assemblies.

Kumar, Meenakshi Sundaram / Stallworth, Karly M / Murthy, Anastasia C / Lim, Su Min / Li, Nan / Jain, Aastha / Munro, James B / Fawzi, Nicolas L / Lagier-Tourenne, Clotilde / Bosco, Daryl A

Journal of molecular biology

2023 Volume 435, Issue 6, Page(s) 167972

Abstract: Deficient nucleocytoplasmic transport is emerging as a pathogenic feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), including in ALS caused by mutations in Fused in Sarcoma (FUS). Recently, both wild-type and ALS-linked ... ...

Abstract	Deficient nucleocytoplasmic transport is emerging as a pathogenic feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), including in ALS caused by mutations in Fused in Sarcoma (FUS). Recently, both wild-type and ALS-linked mutant FUS were shown to directly interact with the phenylalanine-glycine (FG)-rich nucleoporin 62 (Nup62) protein, where FUS WT/ Nup62 interactions were enriched within the nucleus but ALS-linked mutant FUS/ Nup62 interactions were enriched within the cytoplasm of cells. Nup62 is a central channel Nup that has a prominent role in forming the selectivity filter within the nuclear pore complex and in regulating effective nucleocytoplasmic transport. Under conditions where FUS phase separates into liquid droplets in vitro, the addition of Nup62 caused the synergistic formation of amorphous assemblies containing both FUS and Nup62. Here, we examined the molecular determinants of this process using recombinant FUS and Nup62 proteins and biochemical approaches. We demonstrate that the structured C-terminal domain of Nup62 containing an alpha-helical coiled-coil region plays a dominant role in binding FUS and is sufficient for inducing the formation of FUS/Nup62 amorphous assemblies. In contrast, the natively unstructured, F/G repeat-rich N-terminal domain of Nup62 modestly contributed to FUS/Nup62 phase separation behavior. Expression of individual Nup62 domain constructs in human cells confirmed that the Nup62 C-terminal domain is essential for localization of the protein to the nuclear envelope. Our results raise the possibility that interactions between FUS and the C-terminal domain of Nup62 can influence the function of Nup62 under physiological and/or pathological conditions.
MeSH term(s)	Humans ; Active Transport, Cell Nucleus/genetics ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/metabolism ; Cytoplasm/metabolism ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/metabolism ; Mutation ; RNA-Binding Protein FUS/chemistry ; RNA-Binding Protein FUS/metabolism ; Protein Interaction Domains and Motifs ; Membrane Glycoproteins/metabolism ; Nuclear Pore Complex Proteins/metabolism
Chemical Substances	FUS protein, human ; RNA-Binding Protein FUS ; nuclear pore protein p62 ; Membrane Glycoproteins ; Nuclear Pore Complex Proteins
Language	English
Publishing date	2023-01-21
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2023.167972
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Article ; Online: Cryptic splicing of stathmin-2 and UNC13A mRNAs is a pathological hallmark of TDP-43-associated Alzheimer's disease.

Agra Almeida Quadros, Ana Rita / Li, Zhaozhi / Wang, Xue / Ndayambaje, I Sandra / Aryal, Sandeep / Ramesh, Nandini / Nolan, Matthew / Jayakumar, Rojashree / Han, Yi / Stillman, Hannah / Aguilar, Corey / Wheeler, Hayden J / Connors, Theresa / Lopez-Erauskin, Jone / Baughn, Michael W / Melamed, Ze'ev / Beccari, Melinda S / Olmedo Martínez, Laura / Canori, Michael /

Lee, Chao-Zong / Moran, Laura / Draper, Isabelle / Kopin, Alan S / Oakley, Derek H / Dickson, Dennis W / Cleveland, Don W / Hyman, Bradley T / Das, Sudeshna / Ertekin-Taner, Nilüfer / Lagier-Tourenne, Clotilde

Acta neuropathologica

2024 Volume 147, Issue 1, Page(s) 9

Abstract: Nuclear clearance and cytoplasmic accumulations of the RNA-binding protein TDP-43 are pathological hallmarks in almost all patients with amyotrophic lateral sclerosis (ALS) and up to 50% of patients with frontotemporal dementia (FTD) and Alzheimer's ... ...

Abstract	Nuclear clearance and cytoplasmic accumulations of the RNA-binding protein TDP-43 are pathological hallmarks in almost all patients with amyotrophic lateral sclerosis (ALS) and up to 50% of patients with frontotemporal dementia (FTD) and Alzheimer's disease. In Alzheimer's disease, TDP-43 pathology is predominantly observed in the limbic system and correlates with cognitive decline and reduced hippocampal volume. Disruption of nuclear TDP-43 function leads to abnormal RNA splicing and incorporation of erroneous cryptic exons in numerous transcripts including Stathmin-2 (STMN2, also known as SCG10) and UNC13A, recently reported in tissues from patients with ALS and FTD. Here, we identify both STMN2 and UNC13A cryptic exons in Alzheimer's disease patients, that correlate with TDP-43 pathology burden, but not with amyloid-β or tau deposits. We also demonstrate that processing of the STMN2 pre-mRNA is more sensitive to TDP-43 loss of function than UNC13A. In addition, full-length RNAs encoding STMN2 and UNC13A are suppressed in large RNA-seq datasets generated from Alzheimer's disease post-mortem brain tissue. Collectively, these results open exciting new avenues to use STMN2 and UNC13A as potential therapeutic targets in a broad range of neurodegenerative conditions with TDP-43 proteinopathy including Alzheimer's disease.
MeSH term(s)	Humans ; Alzheimer Disease/genetics ; Amyotrophic Lateral Sclerosis ; DNA-Binding Proteins/genetics ; Frontotemporal Dementia ; Pick Disease of the Brain ; RNA Splicing ; RNA, Messenger/genetics ; Stathmin/genetics
Chemical Substances	DNA-Binding Proteins ; RNA, Messenger ; Stathmin ; TARDBP protein, human ; UNC13B protein, human ; STMN2 protein, human
Language	English
Publishing date	2024-01-04
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-023-02655-0
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Article ; Online: Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration.

Neuron

2023 Volume 111, Issue 8, Page(s) 1222–1240.e9

Abstract: Mitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we ... ...

Abstract	Mitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we find that one GSDM family member, GSDME, is expressed by both mouse and human neurons. GSDME plays a role in mitochondrial damage and axon loss. Mitochondrial neurotoxins induced caspase-dependent GSDME cleavage and rapid localization to mitochondria in axons, where GSDME promoted mitochondrial depolarization, trafficking defects, and neurite retraction. Frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS)-associated proteins TDP-43 and PR-50 induced GSDME-mediated damage to mitochondria and neurite loss. GSDME knockdown protected against neurite loss in ALS patient iPSC-derived motor neurons. Knockout of GSDME in SOD1
MeSH term(s)	Mice ; Animals ; Humans ; Amyotrophic Lateral Sclerosis/metabolism ; Gasdermins ; Mice, Knockout ; Motor Neurons/metabolism ; Axons/metabolism
Chemical Substances	Gasdermins
Language	English
Publishing date	2023-03-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	808167-0
ISSN	1097-4199 ; 0896-6273
ISSN (online)	1097-4199
ISSN	0896-6273
DOI	10.1016/j.neuron.2023.02.019
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Article: Somatic Mosaicism in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Reveals Widespread Degeneration from Focal Mutations.

bioRxiv : the preprint server for biology

2023

Abstract: Although mutations in dozens of genes have been implicated in familial forms of amyotrophic lateral sclerosis (fALS) and frontotemporal degeneration (fFTD), most cases of these conditions are sporadic (sALS and sFTD), with no family history, and their ... ...

Abstract	Although mutations in dozens of genes have been implicated in familial forms of amyotrophic lateral sclerosis (fALS) and frontotemporal degeneration (fFTD), most cases of these conditions are sporadic (sALS and sFTD), with no family history, and their etiology remains obscure. We tested the hypothesis that somatic mosaic mutations, present in some but not all cells, might contribute in these cases, by performing ultra-deep, targeted sequencing of 88 genes associated with neurodegenerative diseases in postmortem brain and spinal cord samples from 404 individuals with sALS or sFTD and 144 controls. Known pathogenic germline mutations were found in 20.6% of ALS, and 26.5% of FTD cases. Predicted pathogenic somatic mutations in ALS/FTD genes were observed in 2.7% of sALS and sFTD cases that did not carry known pathogenic or novel germline mutations. Somatic mutations showed low variant allele fraction (typically <2%) and were often restricted to the region of initial discovery, preventing detection through genetic screening in peripheral tissues. Damaging somatic mutations were preferentially enriched in primary motor cortex of sALS and prefrontal cortex of sFTD, mirroring regions most severely affected in each disease. Somatic mutation analysis of bulk RNA-seq data from brain and spinal cord from an additional 143 sALS cases and 23 controls confirmed an overall enrichment of somatic mutations in sALS. Two adult sALS cases were identified bearing pathogenic somatic mutations in
Language	English
Publishing date	2023-12-01
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.11.30.569436
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