scholarly journals Microglial activation in an amyotrophic lateral sclerosis-like model caused by Ranbp2 loss and nucleocytoplasmic transport impairment in retinal ganglion neurons

2018 ◽  
Author(s):  
Kyoung-in Cho ◽  
Dosuk Yoon ◽  
Minzhong Yu ◽  
Neal S Peachey ◽  
Paulo A Ferreira
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
De Novo ◽  
Nucleocytoplasmic Transport ◽  
Retinal Ganglion ◽  
Immune Modulators ◽  
Cell Immunity ◽  
Whole Transcriptome Analysis ◽  
Ganglion Neurons ◽  
Retinal Ganglion Neurons ◽  
Lateral Sclerosis

Nucleocytoplasmic transport is dysregulated in sporadic and familial amyotrophic lateral sclerosis (ALS) and retinal ganglion neurons (RGNs) are purportedly involved in ALS. The Ran-binding protein 2 (Ranbp2) controls rate-limiting steps of nucleocytoplasmic transport. Mice with Ranbp2 loss in Thy1+-motoneurons develop cardinal ALS-like traits, but the impairments in RGNs and the degree of dysfunctional consonance between RGNs and motoneurons caused by Ranbp2 loss are unknown. This understanding will facilitate to discern the role of nucleocytoplasmic transport in the differential vulnerability of neurons to ALS and to develop therapeutic approaches and biomarkers in ALS. Here, we ascertain Ranbp2 function and endophenotypes in RGNs of an ALS-like mouse model lacking Ranbp2 in motoneurons and RGNs. Thy1+-RGNs lacking Ranbp2 shared with motoneurons the dysregulation of nucleocytoplasmic transport. RGN abnormalities were comprised morphologically by soma hypertrophy and optic nerve axonopathy and physiologically by a delay of the visual pathway evoked potentials. Whole-transcriptome analysis showed restricted transcriptional changes in optic nerves that were distinct from those found in sciatic nerves. Specifically, the level and nucleocytoplasmic partition of the anti-apoptotic and novel substrate of Ranbp2, Pttg1/securin, were dysregulated. Further, acetyl-CoA carboxylase 1, which modulates de novo synthesis of fatty acids and T-cell immunity, showed the highest up-regulation (35-fold). This effect was reflected by the activation of ramified Cd11b+ and CD45+-microglia, increase of F4\80+-microglia and a shift from pseudopodial/lamellipodial to amoeboidal F4\80+-microglia intermingled between RGNs of naive mice. This immunogenic phenotype was accompanied by the intracellular sequestration in RGNs of metalloproteinase-28, which regulates macrophage recruitment and polarization in inflammation. Ranbp2 genetic insults in RGNs and motoneurons trigger distinct paracrine signaling likely by the dysregulation of nucleocytoplasmic transport of neural-type selective substrates. Metabolic and immune-modulators underpinning RGN-to-microglial signaling are regulated by Ranbp2, and this neuroglial system manifests endophenotypes that are likely useful in the prognosis and diagnosis of ALS.

scholarly journals Sigma-1 receptor chaperones rescue nucleocytoplasmic transport deficit seen in cellular and Drosophila ALS/FTD models

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Pin-Tse Lee ◽  
Jean-Charles Liévens ◽  
Shao-Ming Wang ◽  
Jian-Ying Chuang ◽  
Bilal Khalil ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Molecular Chaperone ◽  
Nucleocytoplasmic Transport ◽  
Repeat Expansion ◽  
Nuclear Pore ◽  
Sigma 1 Receptor ◽  
Sigma 1 ◽  
Cytoplasmic Accumulation ◽  
Nuclear Pore Assembly ◽  
Lateral Sclerosis

ABSTRACT In a subgroup of patients with amyotrophic lateral sclerosis (ALS)/Frontotemporal dementia (FTD), the (G4C2)-RNA repeat expansion from C9orf72 chromosome binds to the Ran-activating protein (RanGAP) at the nuclear pore, resulting in nucleocytoplasmic transport deficit and accumulation of Ran in the cytosol. Here, we found that the sigma-1 receptor (Sig-1R), a molecular chaperone, reverses the pathological effects of (G4C2)-RNA repeats in cell lines and in Drosophila. The Sig-1R colocalizes with RanGAP and nuclear pore proteins (Nups) and stabilizes the latter. Interestingly, Sig-1Rs directly bind (G4C2)-RNA repeats. Overexpression of Sig-1Rs rescues, whereas the Sig-1R knockout exacerbates, the (G4C2)-RNA repeats-induced aberrant cytoplasmic accumulation of Ran. In Drosophila, Sig-1R (but not the Sig-1R-E102Q mutant) overexpression reverses eye necrosis, climbing deficit, and firing discharge caused by (G4C2)-RNA repeats. These results on a molecular chaperone at the nuclear pore suggest that Sig-1Rs may benefit patients with C9orf72 ALS/FTD by chaperoning the nuclear pore assembly and sponging away deleterious (G4C2)-RNA repeats.

Patient-derived olfactory mucosa cells but not lung or skin fibroblasts mediate axonal regeneration of retinal ganglion neurons

2012 ◽  
Vol 509 (1) ◽  
pp. 27-32 ◽  
Author(s):  
Vega García-Escudero ◽  
Ana García-Gómez ◽  
Elena Langa ◽  
María Jesús Martín-Bermejo ◽  
Rafael Ramírez-Camacho ◽  
...  
Keyword(s):  
Axonal Regeneration ◽  
Olfactory Mucosa ◽  
Skin Fibroblasts ◽  
Retinal Ganglion ◽  
Ganglion Neurons ◽  
Retinal Ganglion Neurons

scholarly journals TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Kathleen M Cunningham ◽  
Kirstin Maulding ◽  
Kai Ruan ◽  
Mumine Senturk ◽  
Jonathan C Grima ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Amyotrophic Lateral Sclerosis ◽  
Nuclear Import ◽  
Transcriptional Regulator ◽  
Nucleocytoplasmic Transport ◽  
Repeat Expansion ◽  
Disease Pathogenesis ◽  
Hexanucleotide Repeat ◽  
Hexanucleotide Repeat Expansion ◽  
Lateral Sclerosis

Disrupted nucleocytoplasmic transport (NCT) has been implicated in neurodegenerative disease pathogenesis; however, the mechanisms by which disrupted NCT causes neurodegeneration remain unclear. In a Drosophila screen, we identified ref(2)P/p62, a key regulator of autophagy, as a potent suppressor of neurodegeneration caused by the GGGGCC hexanucleotide repeat expansion (G4C2 HRE) in C9orf72 that causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that p62 is increased and forms ubiquitinated aggregates due to decreased autophagic cargo degradation. Immunofluorescence and electron microscopy of Drosophila tissues demonstrate an accumulation of lysosome-like organelles that precedes neurodegeneration. These phenotypes are partially caused by cytoplasmic mislocalization of Mitf/TFEB, a key transcriptional regulator of autophagolysosomal function. Additionally, TFEB is mislocalized and downregulated in human cells expressing GGGGCC repeats and in C9-ALS patient motor cortex. Our data suggest that the C9orf72-HRE impairs Mitf/TFEB nuclear import, thereby disrupting autophagy and exacerbating proteostasis defects in C9-ALS/FTD.

scholarly journals Modulation of actin polymerization affects nucleocytoplasmic transport in multiple forms of amyotrophic lateral sclerosis

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Anthony Giampetruzzi ◽  
Eric W. Danielson ◽  
Valentina Gumina ◽  
Maryangel Jeon ◽  
Sivakumar Boopathy ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Actin Polymerization ◽  
Nucleocytoplasmic Transport ◽  
Multiple Forms ◽  
Lateral Sclerosis

Retinal ganglion neurons express a toxin-resistant developmentally regulated novel type of high-voltage-activated calcium channel

1994 ◽  
Vol 72 (5) ◽  
pp. 2542-2546 ◽  
Author(s):  
T. Rothe ◽  
R. Grantyn
Keyword(s):  
High Voltage ◽  
Channel Blocker ◽  
Retinal Ganglion ◽  
The Novel ◽  
Developmentally Regulated ◽  
Electrophysiological Measurements ◽  
Ganglion Neurons ◽  
Retinal Ganglion Neurons ◽  
Developmental Analysis

1. High-voltage-activated Ca2+ currents [ICa(HVA)] were studied in immunolabeled mouse retinal ganglion neurons (RGNs) to elucidate channel-specific components and their developmental changes in vitro. 2. Neurons were dissociated at postnatal day 5. RGNs were selected for electrophysiological measurements by vital labeling with an antibody against Thy-1.2. ICa(HVA) were recorded with patch electrodes in the whole cell configuration at a holding voltage (Vh) of -90 mV. 3. A total of 111 neurons was studied. On average, 13% of ICa(HVA) was reversibly blocked by 10 microM nifedipine, approximately 30% of the compound current displayed an irreversible block by 2.5 microM omega-conotoxin (omega-CTX) GVIA. The remainder current was resistant to both drugs, suggesting that the total ICa(HVA) was a mixture of at least three different components. 4. Developmental analysis revealed a significant increase of the omega-CTX-GVIA/nifedipine-resistant component of ICa(HVA) (31% at day in vitro (DIV) 0–2, 70% at DIV 18–26) mainly at the expense of the omega-CTX-GVIA-sensitive current. No significant change was found in the nifedipine-sensitive component of ICa(HVA). 5. To characterize the Ca2+ current component that was resistant to both omega-CTX-GVIA and nifedipine at Vh -90 mV, three tests were performed. The P channel antagonist omega-agatoxin IVA (omega-Aga-IVA, 200 nM) completely failed to block ICa(HVA) in mouse RGNs. The novel Ca2+ channel blocker omega-CTX-MVIIC (5 microM) decreased the ICa(HVA) remaining after omega-CTX-GVIA treatment by only approximately 10%.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Modulation of actin polymerization affects nucleocytoplasmic transport in multiple forms of Amyotrophic Lateral Sclerosis

2018 ◽  
Author(s):  
Anthony Giampetruzzi ◽  
Eric W. Danielson ◽  
Maryangel Jeon ◽  
Valentia Gumina ◽  
Sivakumar Boopathy ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Actin Polymerization ◽  
Molecular Mechanisms ◽  
Nucleocytoplasmic Transport ◽  
Unknown Etiology ◽  
Nuclear Pore ◽  
Repeat Expansions ◽  
Lateral Sclerosis ◽  
Actin Homeostasis

ABSTRACTAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of unknown etiology. Although defects in nucleocytoplasmic transport (NCT) may be central to the pathogenesis of ALS and other neurodegenerative diseases, the molecular mechanisms modulating the nuclear pore function are still largely unknown. Here we show that genetic and pharmacological modulation of actin polymerization disrupts nuclear pore integrity, nuclear import, and downstream pathways such as mRNA post-transcriptional regulation. Importantly, we demonstrate that modulation of actin homeostasis can rescue nuclear pore instability and dysfunction caused by mutant PFN1 as well as by C9ORF72 repeat expansions, the most common mutations in ALS patients. Collectively, our data link NCT defects to ALS-associated pathology and propose the regulation of actin homeostasis as a novel therapeutic strategy for ALS and other neurodegenerative diseases.

scholarly journals TFEB/Mitf links impaired nuclear import to autophagolysosomal dysfunction in C9-ALS

2020 ◽  
Author(s):  
Kathleen M. Cunningham ◽  
Ke Zhang ◽  
Kai Ruan ◽  
Kirstin Maulding ◽  
Mumine Senturk ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Amyotrophic Lateral Sclerosis ◽  
Nuclear Import ◽  
Transcriptional Regulator ◽  
Nucleocytoplasmic Transport ◽  
Repeat Expansion ◽  
Disease Pathogenesis ◽  
Hexanucleotide Repeat ◽  
Hexanucleotide Repeat Expansion ◽  
Lateral Sclerosis

AbstractDisrupted nucleocytoplasmic transport (NCT) has been implicated in neurodegenerative disease pathogenesis; however, the mechanisms by which impaired NCT causes neurodegeneration remain unclear. In a Drosophila screen, we identified Ref(2)p/p62, a key regulator of autophagy, as a potent suppressor of neurodegeneration caused by the GGGGCC hexanucleotide repeat expansion (G4C2 HRE) in C9orf72 that causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We found that p62 is increased and forms ubiquitinated aggregates due to decreased autophagic cargo degradation. Immunofluorescence and electron microscopy of Drosophila tissues demonstrate an accumulation of lysosome-like organelles that precedes neurodegeneration. These phenotypes are partially caused by cytoplasmic mislocalization of Mitf/TFEB, a key transcriptional regulator of autophagolysosomal function. Additionally, TFEB is mislocalized and downregulated in human cells expressing GGGGCC repeats and in C9-ALS patient motor cortex. Our data suggest that the C9orf72-HRE impairs Mitf/TFEB nuclear import, thereby disrupting autophagy and exacerbating proteostasis defects in C9-ALS/FTD.

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