The Experts below are selected from a list of 4701 Experts worldwide ranked by ideXlab platform
Jonathan C. Grima - One of the best experts on this subject based on the ideXlab platform.
-
stress granule assembly disrupts Nucleocytoplasmic Transport
Cell, 2018Co-Authors: Ke Zhang, Jonathan C. Grima, Kathleen M. Cunningham, Gavin J Daigle, Alyssa N Coyne, Kai Ruan, Kelly Bowen, Harsh Wadhwa, Peiguo Yang, Frank RigoAbstract:Defects in Nucleocytoplasmic Transport have been identified as a key pathogenic event in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mediated by a GGGGCC hexanucleotide repeat expansion in C9ORF72, the most common genetic cause of ALS/FTD. Furthermore, Nucleocytoplasmic Transport disruption has also been implicated in other neurodegenerative diseases with protein aggregation, suggesting a shared mechanism by which protein stress disrupts Nucleocytoplasmic Transport. Here, we show that cellular stress disrupts Nucleocytoplasmic Transport by localizing critical Nucleocytoplasmic Transport factors into stress granules, RNA/protein complexes that play a crucial role in ALS pathogenesis. Importantly, inhibiting stress granule assembly, such as by knocking down Ataxin-2, suppresses Nucleocytoplasmic Transport defects as well as neurodegeneration in C9ORF72-mediated ALS/FTD. Our findings identify a link between stress granule assembly and Nucleocytoplasmic Transport, two fundamental cellular processes implicated in the pathogenesis of C9ORF72-mediated ALS/FTD and other neurodegenerative diseases.
-
tau protein disrupts Nucleocytoplasmic Transport in alzheimer s disease
Social Science Research Network, 2018Co-Authors: Bahareh Eftekharzadeh, Jonathan C. Grima, Sean J. Miller, Rachel E Bennett, Gavin J Daigle, Larisa E Kapinos, Simon Dujardin, Alyssa Coyne, Casey Cook, Julia SchiantarelliAbstract:Tau protein, which normally functions to stabilize microtubules, is the major constituent of neurofibrillary tangles in Alzheimer’s disease (AD). The mechanism underlying tau-associated neural damage remains unclear. We now show that tau can interact with nuclear pore complex (NPC) constituents and affect their structural and functional integrity. Pathological tau leads to dissociation of nuclear pore complex proteins, and impairs nuclear export and import in vitro, in tau overexpressing transgenic mouse models, and in human AD tissue. Moreover, a nuclear pore component, Nup98, surprisingly colocalizes with neurofibrillary tangles in neuronal soma, and both in vivo and in vitro directly interacts with tau to greatly facilitate its aggregation. These data support the hypothesis that tau directly interacts with nuclear pore complex constituents, leading to their mislocalization and to disruption of nuclear pore function, raising the possibility that nuclear pore dysfunction contributes to tau-induced neurotoxicity in Alzheimer’s disease.
-
mutant huntingtin disrupts the nuclear pore complex
Neuron, 2017Co-Authors: Jonathan C. Grima, Ke Zhang, Gavin J Daigle, Nicolas Arbez, Kathleen C Cunningham, Joseph Ochaba, Charlene Geater, Eva L Morozko, Jennifer Stocksdale, Jenna C GlatzerAbstract:Summary Huntington's disease (HD) is caused by an expanded CAG repeat in the Huntingtin ( HTT ) gene. The mechanism(s) by which mutant HTT (mHTT) causes disease is unclear. Nucleocytoplasmic Transport, the trafficking of macromolecules between the nucleus and cytoplasm, is tightly regulated by nuclear pore complexes (NPCs) made up of nucleoporins (NUPs). Previous studies offered clues that mHTT may disrupt Nucleocytoplasmic Transport and a mutation of an NUP can cause HD-like pathology. Therefore, we evaluated the NPC and Nucleocytoplasmic Transport in multiple models of HD, including mouse and fly models, neurons transfected with mHTT , HD iPSC-derived neurons, and human HD brain regions. These studies revealed severe mislocalization and aggregation of NUPs and defective Nucleocytoplasmic Transport. HD repeat-associated non-ATG (RAN) translation proteins also disrupted Nucleocytoplasmic Transport. Additionally, overexpression of NUPs and treatment with drugs that prevent aberrant NUP biology also mitigated this Transport defect and neurotoxicity, providing future novel therapy targets.
-
c9orf72 poly ga aggregates sequester and impair hr23 and Nucleocytoplasmic Transport proteins
Nature Neuroscience, 2016Co-Authors: Yong Jie Zhang, Jonathan C. Grima, Tania D Gendron, Hiroki Sasaguri, Karen Jansenwest, Rebecca B Katzman, Jennifer Gass, Melissa E Murray, Mitsuru Shinohara, Wen Lang LinAbstract:Neuronal inclusions of poly(GA), a protein unconventionally translated from G4C2 repeat expansions in C9ORF72, are abundant in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by this mutation. To investigate poly(GA) toxicity, we generated mice that exhibit poly(GA) pathology, neurodegeneration and behavioral abnormalities reminiscent of FTD and ALS. These phenotypes occurred in the absence of TDP-43 pathology and required poly(GA) aggregation. HR23 proteins involved in proteasomal degradation and proteins involved in Nucleocytoplasmic Transport were sequestered by poly(GA) in these mice. HR23A and HR23B similarly colocalized to poly(GA) inclusions in C9ORF72 expansion carriers. Sequestration was accompanied by an accumulation of ubiquitinated proteins and decreased xeroderma pigmentosum C (XPC) levels in mice, indicative of HR23A and HR23B dysfunction. Restoring HR23B levels attenuated poly(GA) aggregation and rescued poly(GA)-induced toxicity in neuronal cultures. These data demonstrate that sequestration and impairment of nuclear HR23 and Nucleocytoplasmic Transport proteins is an outcome of, and a contributor to, poly(GA) pathology.
-
The C9orf72 repeat expansion disrupts Nucleocytoplasmic Transport
Nature, 2015Co-Authors: Ke Zhang, Christopher J. Donnelly, Aaron R. Haeusler, Jonathan C. Grima, James B. Machamer, Peter Steinwald, Elizabeth L. Daley, Sean J. Miller, Kathleen M. Cunningham, Svetlana VidenskyAbstract:The hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G4C2 RNA including RanGAP1. A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of Nucleocytoplasmic Transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic Transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.
Gavin J Daigle - One of the best experts on this subject based on the ideXlab platform.
-
stress granule assembly disrupts Nucleocytoplasmic Transport
Cell, 2018Co-Authors: Ke Zhang, Jonathan C. Grima, Kathleen M. Cunningham, Gavin J Daigle, Alyssa N Coyne, Kai Ruan, Kelly Bowen, Harsh Wadhwa, Peiguo Yang, Frank RigoAbstract:Defects in Nucleocytoplasmic Transport have been identified as a key pathogenic event in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mediated by a GGGGCC hexanucleotide repeat expansion in C9ORF72, the most common genetic cause of ALS/FTD. Furthermore, Nucleocytoplasmic Transport disruption has also been implicated in other neurodegenerative diseases with protein aggregation, suggesting a shared mechanism by which protein stress disrupts Nucleocytoplasmic Transport. Here, we show that cellular stress disrupts Nucleocytoplasmic Transport by localizing critical Nucleocytoplasmic Transport factors into stress granules, RNA/protein complexes that play a crucial role in ALS pathogenesis. Importantly, inhibiting stress granule assembly, such as by knocking down Ataxin-2, suppresses Nucleocytoplasmic Transport defects as well as neurodegeneration in C9ORF72-mediated ALS/FTD. Our findings identify a link between stress granule assembly and Nucleocytoplasmic Transport, two fundamental cellular processes implicated in the pathogenesis of C9ORF72-mediated ALS/FTD and other neurodegenerative diseases.
-
tau protein disrupts Nucleocytoplasmic Transport in alzheimer s disease
Social Science Research Network, 2018Co-Authors: Bahareh Eftekharzadeh, Jonathan C. Grima, Sean J. Miller, Rachel E Bennett, Gavin J Daigle, Larisa E Kapinos, Simon Dujardin, Alyssa Coyne, Casey Cook, Julia SchiantarelliAbstract:Tau protein, which normally functions to stabilize microtubules, is the major constituent of neurofibrillary tangles in Alzheimer’s disease (AD). The mechanism underlying tau-associated neural damage remains unclear. We now show that tau can interact with nuclear pore complex (NPC) constituents and affect their structural and functional integrity. Pathological tau leads to dissociation of nuclear pore complex proteins, and impairs nuclear export and import in vitro, in tau overexpressing transgenic mouse models, and in human AD tissue. Moreover, a nuclear pore component, Nup98, surprisingly colocalizes with neurofibrillary tangles in neuronal soma, and both in vivo and in vitro directly interacts with tau to greatly facilitate its aggregation. These data support the hypothesis that tau directly interacts with nuclear pore complex constituents, leading to their mislocalization and to disruption of nuclear pore function, raising the possibility that nuclear pore dysfunction contributes to tau-induced neurotoxicity in Alzheimer’s disease.
-
mutant huntingtin disrupts the nuclear pore complex
Neuron, 2017Co-Authors: Jonathan C. Grima, Ke Zhang, Gavin J Daigle, Nicolas Arbez, Kathleen C Cunningham, Joseph Ochaba, Charlene Geater, Eva L Morozko, Jennifer Stocksdale, Jenna C GlatzerAbstract:Summary Huntington's disease (HD) is caused by an expanded CAG repeat in the Huntingtin ( HTT ) gene. The mechanism(s) by which mutant HTT (mHTT) causes disease is unclear. Nucleocytoplasmic Transport, the trafficking of macromolecules between the nucleus and cytoplasm, is tightly regulated by nuclear pore complexes (NPCs) made up of nucleoporins (NUPs). Previous studies offered clues that mHTT may disrupt Nucleocytoplasmic Transport and a mutation of an NUP can cause HD-like pathology. Therefore, we evaluated the NPC and Nucleocytoplasmic Transport in multiple models of HD, including mouse and fly models, neurons transfected with mHTT , HD iPSC-derived neurons, and human HD brain regions. These studies revealed severe mislocalization and aggregation of NUPs and defective Nucleocytoplasmic Transport. HD repeat-associated non-ATG (RAN) translation proteins also disrupted Nucleocytoplasmic Transport. Additionally, overexpression of NUPs and treatment with drugs that prevent aberrant NUP biology also mitigated this Transport defect and neurotoxicity, providing future novel therapy targets.
Ke Zhang - One of the best experts on this subject based on the ideXlab platform.
-
stress granule assembly disrupts Nucleocytoplasmic Transport
Cell, 2018Co-Authors: Ke Zhang, Jonathan C. Grima, Kathleen M. Cunningham, Gavin J Daigle, Alyssa N Coyne, Kai Ruan, Kelly Bowen, Harsh Wadhwa, Peiguo Yang, Frank RigoAbstract:Defects in Nucleocytoplasmic Transport have been identified as a key pathogenic event in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mediated by a GGGGCC hexanucleotide repeat expansion in C9ORF72, the most common genetic cause of ALS/FTD. Furthermore, Nucleocytoplasmic Transport disruption has also been implicated in other neurodegenerative diseases with protein aggregation, suggesting a shared mechanism by which protein stress disrupts Nucleocytoplasmic Transport. Here, we show that cellular stress disrupts Nucleocytoplasmic Transport by localizing critical Nucleocytoplasmic Transport factors into stress granules, RNA/protein complexes that play a crucial role in ALS pathogenesis. Importantly, inhibiting stress granule assembly, such as by knocking down Ataxin-2, suppresses Nucleocytoplasmic Transport defects as well as neurodegeneration in C9ORF72-mediated ALS/FTD. Our findings identify a link between stress granule assembly and Nucleocytoplasmic Transport, two fundamental cellular processes implicated in the pathogenesis of C9ORF72-mediated ALS/FTD and other neurodegenerative diseases.
-
mutant huntingtin disrupts the nuclear pore complex
Neuron, 2017Co-Authors: Jonathan C. Grima, Ke Zhang, Gavin J Daigle, Nicolas Arbez, Kathleen C Cunningham, Joseph Ochaba, Charlene Geater, Eva L Morozko, Jennifer Stocksdale, Jenna C GlatzerAbstract:Summary Huntington's disease (HD) is caused by an expanded CAG repeat in the Huntingtin ( HTT ) gene. The mechanism(s) by which mutant HTT (mHTT) causes disease is unclear. Nucleocytoplasmic Transport, the trafficking of macromolecules between the nucleus and cytoplasm, is tightly regulated by nuclear pore complexes (NPCs) made up of nucleoporins (NUPs). Previous studies offered clues that mHTT may disrupt Nucleocytoplasmic Transport and a mutation of an NUP can cause HD-like pathology. Therefore, we evaluated the NPC and Nucleocytoplasmic Transport in multiple models of HD, including mouse and fly models, neurons transfected with mHTT , HD iPSC-derived neurons, and human HD brain regions. These studies revealed severe mislocalization and aggregation of NUPs and defective Nucleocytoplasmic Transport. HD repeat-associated non-ATG (RAN) translation proteins also disrupted Nucleocytoplasmic Transport. Additionally, overexpression of NUPs and treatment with drugs that prevent aberrant NUP biology also mitigated this Transport defect and neurotoxicity, providing future novel therapy targets.
-
The C9orf72 repeat expansion disrupts Nucleocytoplasmic Transport
Nature, 2015Co-Authors: Ke Zhang, Christopher J. Donnelly, Aaron R. Haeusler, Jonathan C. Grima, James B. Machamer, Peter Steinwald, Elizabeth L. Daley, Sean J. Miller, Kathleen M. Cunningham, Svetlana VidenskyAbstract:The hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G4C2 RNA including RanGAP1. A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of Nucleocytoplasmic Transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic Transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.
Ana Jovicic - One of the best experts on this subject based on the ideXlab platform.
-
nuclear Transport dysfunction a common theme in amyotrophic lateral sclerosis and frontotemporal dementia
Journal of Neurochemistry, 2016Co-Authors: Ana Jovicic, Joseph W Paul, Aaron D GitlerAbstract:Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with overlapping genetic factors and pathology. On the cellular level, a majority of ALS and FTD cases are characterized by nuclear clearance and cytoplasmic aggregation of otherwise nuclear proteins, TAR DNA-binding protein 43 (TDP-43), or fused in sarcoma. Recent studies investigating cellular pathways perturbed by genetic risk factors for ALS/FTD converge on Nucleocytoplasmic Transport dysfunction as a mechanism leading to disease pathophysiology. We propose that mutations in FUS and hexanucleotide expansions in C9orf72 and aging all converge on the impairment of Nucleocytoplasmic Transport, which results in the hallmark pathological feature of ALS/FTD - cytoplasmic aggregation of TDP-43 or FUS.
-
modifiers of c9orf72 dipeptide repeat toxicity connect Nucleocytoplasmic Transport defects to ftd als
Nature Neuroscience, 2015Co-Authors: Ana Jovicic, Jerome Mertens, Steven Boeynaems, Elke Bogaert, Noori Chai, Shizuka B Yamada, Joseph W Paul, Shuying Sun, Joseph R Herdy, Gregor BieriAbstract:C9orf72 mutations are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Dipeptide repeat proteins (DPRs) produced by unconventional translation of the C9orf72 repeat expansions cause neurodegeneration in cell culture and in animal models. We performed two unbiased screens in Saccharomyces cerevisiae and identified potent modifiers of DPR toxicity, including karyopherins and effectors of Ran-mediated Nucleocytoplasmic Transport, providing insight into potential disease mechanisms and therapeutic targets.
Claudia Fallini - One of the best experts on this subject based on the ideXlab platform.
-
modulation of actin polymerization affects Nucleocytoplasmic Transport in multiple forms of amyotrophic lateral sclerosis
Nature Communications, 2019Co-Authors: Anthony Giampetruzzi, John Landers, Eric Danielson, Maryangel Jeon, Valentina Gumina, Sivakumar Boopathy, Robert H Brown, Antonia Ratti, Claudia FalliniAbstract:Amyotrophic 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 expansion, the most common mutation in ALS patients. Collectively, our data link NCT defects to ALS-associated cellular pathology and propose the regulation of actin homeostasis as a novel therapeutic strategy for ALS and other neurodegenerative diseases.
-
the rna binding protein fus tls undergoes calcium mediated nuclear egress during excitotoxic stress and is required for gria2 mrna processing
Journal of Biological Chemistry, 2019Co-Authors: Maeve Tischbein, Desiree M Baron, Yenchen Lin, Katherine V Gall, John Landers, Claudia Fallini, Daryl A BoscoAbstract:Excitotoxic levels of glutamate represent a physiological stress that is strongly linked to amyotrophic lateral sclerosis (ALS) and other neurological disorders. Emerging evidence indicates a role for neurodegenerative disease-linked RNA-binding proteins (RBPs) in the cellular stress response. However, the relationships between excitotoxicity, RBP function, and disease have not been explored. Here, using primary cortical and motor neurons, we found that excitotoxicity induced the translocation of select ALS-linked RBPs from the nucleus to the cytoplasm within neurons. RBPs affected by excitotoxicity included TAR DNA-binding protein 43 (TDP-43) and, most robustly, fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS). We noted that FUS is translocated through a calcium-dependent mechanism and that its translocation coincides with striking alterations in Nucleocytoplasmic Transport. Furthermore, glutamate-induced up-regulation of glutamate ionotropic receptor α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type subunit 2 (GRIA2) in neurons depended on FUS expression, consistent with a functional role for FUS in excitotoxic stress. These findings reveal molecular links among prominent factors in neurodegenerative diseases, namely excitotoxicity, disease-associated RBPs, and Nucleocytoplasmic Transport.
-
modulation of actin polymerization affects Nucleocytoplasmic Transport in multiple forms of amyotrophic lateral sclerosis
bioRxiv, 2018Co-Authors: Anthony Giampetruzzi, John Landers, Eric Danielson, Maryangel Jeon, Valentina Gumina, Sivakumar Boopathy, Robert H Brown, Claudia FalliniAbstract:Amyotrophic 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.
-
fus tls undergoes calcium mediated nuclear egress during excitotoxic stress and is required for gria2 mrna processing
bioRxiv, 2018Co-Authors: Maeve Tischbein, Desiree M Baron, Yenchen Lin, Katherine V Gall, John Landers, Claudia Fallini, Daryl A BoscoAbstract:Excitotoxic levels of glutamate represent a physiological stress that is strongly linked to amyotrophic lateral sclerosis (ALS) and other neurological disorders. Emerging evidence indicates a role for neurodegenerative disease linked RNA-binding proteins (RBPs) in the cellular stress response. However, the relationships between excitotoxicity, RBP function and pathology have not been explored. Here, we found that excitotoxicity induced the translocation of select ALS-linked RBPs from the nucleus to the cytoplasm within neurons. RBPs affected by excitotoxicity include TAR DNA-binding protein 43 (TDP-43) and, most robustly, fused in sarcoma/translocated in liposarcoma (FUS/TLS). FUS translocation occurs through a calcium-dependent mechanism and coincides with striking alterations in Nucleocytoplasmic Transport. Further, glutamate-induced upregulation of Gria2 in neurons was dependent on FUS expression, consistent with a functional role for FUS under excitotoxic stress. These findings reveal a link between prominent factors in neurodegenerative disease, namely excitotoxicity, disease-associated RBPs and Nucleocytoplasmic Transport.
