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.

Sigma 1 receptor as a therapeutic target for amyotrophic lateral sclerosis

2020 ◽  
Author(s):  
Mireia Herrando‐Grabulosa ◽  
Núria Gaja‐Capdevila ◽  
José M. Vela ◽  
Xavier Navarro
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Therapeutic Target ◽  
Sigma 1 Receptor ◽  
Sigma 1 ◽  
Lateral Sclerosis

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

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.

scholarly journals Role of the Sigma-1 receptor in Amyotrophic Lateral Sclerosis (ALS)

2015 ◽  
Vol 127 (1) ◽  
pp. 10-16 ◽  
Author(s):  
Timur A. Mavlyutov ◽  
Lian-Wang Guo ◽  
Miles L. Epstein ◽  
Arnold E. Ruoho
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Sigma 1 Receptor ◽  
Sigma 1 ◽  
Lateral Sclerosis

scholarly journals Sigma-1 receptor is a key genetic modulator in amyotrophic lateral sclerosis

2019 ◽  
Author(s):  
Simon Couly ◽  
Bilal Khalil ◽  
Véronique Viguier ◽  
Julien Roussel ◽  
Tangui Maurice ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
High Energy ◽  
Dependent Manner ◽  
Wild Type ◽  
Sigma 1 Receptor ◽  
Atp Levels ◽  
Sigma 1 ◽  
Lateral Sclerosis

Abstract Sigma-1 receptor (S1R) is an endoplasmic reticulum (ER) chaperone that regulates mitochondrial respiration but also controls cellular defense against ER and oxidative stress. This makes S1R a potential therapeutic target in amyotrophic lateral sclerosis (ALS). Especially, as a missense mutation E102Q in S1R has been reported in few familial ALS cases. However, the pathogenicity of S1RE102Q and the beneficial impact of S1R in the ALS context remain to be demonstrated in vivo. To address this, we generated transgenic Drosophila that express human wild-type S1R or S1RE102Q. Expression of mutant S1R in fly neurons induces abnormal eye morphology and locomotor defects in a dose-dependent manner. This was accompanied by abnormal mitochondrial fragmentation, reduced ATP levels and a higher fatigability at the neuromuscular junction during high energy demand. Overexpressing IP3 receptor or glucose transporter mitigates the S1RE102Q-induced eye phenotype, further highlighting the role of calcium and energy metabolism in its toxicity. More importantly, we showed that wild-type S1R rescues locomotor activity and ATP levels of flies expressing the key ALS protein, TDP43. Moreover, overexpressing wild-type S1R enhances resistance of flies to oxidative stress. Therefore, our data provide the first genetic evidence that mutant S1R recapitulates ALS pathology in vivo while increasing S1R confers neuroprotection against TDP43 toxicity.

SA4503, a sigma-1 receptor agonist, suppresses motor neuron damage in in vitro and in vivo amyotrophic lateral sclerosis models

2014 ◽  
Vol 559 ◽  
pp. 174-178 ◽  
Author(s):  
Yoko Ono ◽  
Hirotaka Tanaka ◽  
Masafumi Takata ◽  
Yuki Nagahara ◽  
Yasuhiro Noda ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Receptor Agonist ◽  
Sigma 1 Receptor ◽  
Sigma 1 ◽  
Neuron Damage ◽  
Lateral Sclerosis

scholarly journals Coexistence of neuronal intranuclear inclusion disease and amyotrophic lateral sclerosis: an autopsy case

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Atsuhiko Sugiyama ◽  
Takahiro Takeda ◽  
Mizuho Koide ◽  
Hajime Yokota ◽  
Hiroki Mukai ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Brain Mri ◽  
Brain Magnetic Resonance Imaging ◽  
Repeat Expansion ◽  
Cerebellar Hemisphere ◽  
Intranuclear Inclusions ◽  
Intranuclear Inclusion ◽  
Neuronal Intranuclear Inclusion ◽  
Lateral Sclerosis

Abstract Background Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease. Pathologically, it is characterized by eosinophilic hyaline intranuclear inclusions in the cells of the visceral organs as well as central, peripheral, and autonomic nervous system cells. Recently, a GGC repeat expansion in the NOTCH2NLC gene has been identified as the etiopathological agent of NIID. Interestingly, this GGC repeat expansion was also reported in some patients with a clinical diagnosis of amyotrophic lateral sclerosis (ALS). However, there are no autopsy-confirmed cases of concurrent NIID and ALS. Case presentation A 60-year-old Taiwanese woman reported a four-month history of progressive weakness beginning in the right foot that spread to all four extremities. She was diagnosed with ALS because she met the revised El Escorial diagnostic criteria for definite ALS with upper and lower motor neuron involvement in the cervical, thoracic, and lumbosacral regions. She died of respiratory failure at 22 months from ALS onset, at the age of 62 years. Brain magnetic resonance imaging (MRI) revealed lesions in the medial part of the cerebellar hemisphere, right beside the vermis (paravermal lesions). The subclinical neuropathy, indicated by a nerve conduction study (NCS), prompted a potential diagnosis of NIID. Antemortem skin biopsy and autopsy confirmed the coexistence of pathology consistent with both ALS and NIID. We observed neither eccentric distribution of p62-positive intranuclear inclusions in the areas with abundant large motor neurons nor cytopathological coexistence of ALS and NIID pathology in motor neurons. This finding suggested that ALS and NIID developed independently in this patient. Conclusions We describe a case of concurrent NIID and ALS discovered during an autopsy. Abnormal brain MRI findings, including paravermal lesions, could indicate the coexistence of NIID even in patients with ALS showing characteristic clinical phenotypes.

Sign in / Sign up

Export Citation Format

Share Document