@article{pmid42399454,

title = {GATOR1 signaling defects promote astrocytic metabolic rewiring and excitatory neurotransmitter cycling},

author = {Imane Hadj-Aissa and Maéline Muller and Jorge Soliz and Chantelle F Sephton and Paul A Dutchak},

doi = {10.1038/s44319-026-00846-w},

issn = {1469-3178},

year  = {2026},

date = {2026-07-01},

journal = {EMBO Rep},

abstract = {GATOR1 is an evolutionarily-conserved negative regulator of mTORC1-dependent signal transduction with pathogenic mutations linked to epilepsy, infantile spasms, and autism spectrum disorders. While a biochemical role of GATOR1 in amino acid-signaling is established, its cell-type specific contributions within the brain remain poorly defined. Here, we show that loss of GATOR1 function in astrocytic cells disrupts mitochondrial metabolism, with a selective dysfunction of the electron transport chain Complex II leading to elevated reactive oxygen species (ROS) and redox imbalance. These changes are accompanied by compensatory increases in antioxidant regulatory systems including superoxide dismutase, but remain insufficient to ameliorate the increased ROS. GATOR1-deficient astrocytes show metabolic rewiring marked by enhanced expression of glutamate uptake and glutamine synthesis pathways that contribute to the glutamate-glutamine cycle governing neuronal glutamine availability and synaptic homeostasis. In vivo, GATOR1 deficiency results in progressive astrocytic reactivity, seizures, and a reduced lifespan. These findings demonstrate that GATOR1 function is critical to coordinate astrocytic mitochondrial activity and neurotransmitter cycling pathways, establishing a novel link between intracellular amino acid-signaling in astrocytes and excitatory neural network homeostasis.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40971894,

title = {Targeting lipid droplets in FUS-linked amyotrophic lateral sclerosis mitigates neuronal and astrocytic lipotoxicity},

author = {Laetitia Marcadet and Mari Carmen Pelaez and Antoine Desmeules and Jeanne Serrano and Zhan Cheng and Sahara Khademullah and Elahe Parham and Jaimee Kennedy and Claire Troakes and Caroline Vance and Jorge Soliz and Heather D Durham and Liang Li and Paul A Dutchak and Chantelle F Sephton},

doi = {10.1093/brain/awaf328},

issn = {1460-2156},

year  = {2025},

date = {2025-09-01},

journal = {Brain},

abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons, muscle atrophy, and systemic energy imbalance. Increasing evidence suggests a metabolic shift in ALS from glucose metabolism toward fatty acid utilization; however, the downstream consequences of this reprogramming on disease progression and neuropathology remain poorly defined. We investigated neurometabolic changes in ALS using in vitro and in vivo models of familial ALS expressing the human fused in sarcoma variant R521G (hFUSR521G), along with post-mortem spinal cord tissue from ALS-FUS cases. A combination of unbiased quantitative metabolomic profiling, immunolabeling, and biochemical and molecular approaches were employed. Mass spectrometry of cortical tissue from hFUSR521G mice and littermates revealed a significant increase in acylcarnitine moieties, key substrates used in mitochondrial β-oxidation and cellular energy production. Complementary cytohistological analyses in hFUSR521G mice demonstrated increased lipid droplets (LDs) and peroxidized lipids in both neurons and astrocytes, consistent with our post-mortem findings in spinal cords of individuals carrying FUS R495X or K510E mutations. Arimoclomol, previously shown to ameliorate behavioral phenotypes in this ALS mouse model, was found to enhance lipid metabolism and reduce lipotoxicity in hFUSR521G mice and in cultured neurons and astrocytes expressing FUS R521G. Mechanistically, arimoclomol enhanced LD-mitochondrial contacts and stimulated mitochondrial β-oxidation-dependent lipid catabolism under both basal and pro-inflammatory conditions. This effect was abrogated by etomoxir, an irreversible inhibitor of CPT1, the rate-limiting enzyme of the carnitine shuttle, highlighting a CPT1-dependent mechanism for lipid mobilization. Together, these findings reveal a previously unrecognized role for mitochondrial lipid metabolism in ALS pathogenesis and identify a therapeutic pathway for mitigating the cytotoxic consequences of lipid and acylcarnitine accumulation in FUS-associated ALS.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38396745,

title = {GATOR1 Mutations Impair PI3 Kinase-Dependent Growth Factor Signaling Regulation of mTORC1},

author = {Maéline Muller and Jasmine Bélanger and Imane Hadj-Aissa and Conghao Zhang and Chantelle F Sephton and Paul A Dutchak},

doi = {10.3390/ijms25042068},

issn = {1422-0067},

year  = {2024},

date = {2024-02-01},

journal = {Int J Mol Sci},

volume = {25},

number = {4},

abstract = {GATOR1 (GAP Activity TOward Rag 1) is an evolutionarily conserved GTPase-activating protein complex that controls the activity of mTORC1 (mammalian Target Of Rapamycin Complex 1) in response to amino acid availability in cells. Genetic mutations in the GATOR1 subunits, NPRL2 (nitrogen permease regulator-like 2), NPRL3 (nitrogen permease regulator-like 3), and DEPDC5 (DEP domain containing 5), have been associated with epilepsy in humans; however, the specific effects of these mutations on GATOR1 function and mTORC1 regulation are not well understood. Herein, we report that epilepsy-linked mutations in the NPRL2 subunit of GATOR1, NPRL2-L105P, -T110S, and -D214H, increase basal mTORC1 signal transduction in cells. Notably, we show that NPRL2-L105P is a loss-of-function mutation that disrupts protein interactions with NPRL3 and DEPDC5, impairing GATOR1 complex assembly and resulting in high mTORC1 activity even under conditions of amino acid deprivation. Furthermore, our studies reveal that the GATOR1 complex is necessary for the rapid and robust inhibition of mTORC1 in response to growth factor withdrawal or pharmacological inhibition of phosphatidylinositol-3 kinase (PI3K). In the absence of the GATOR1 complex, cells are refractory to PI3K-dependent inhibition of mTORC1, permitting sustained translation and restricting the nuclear localization of TFEB, a transcription factor regulated by mTORC1. Collectively, our results show that epilepsy-linked mutations in NPRL2 can block GATOR1 complex assembly and restrict the appropriate regulation of mTORC1 by canonical PI3K-dependent growth factor signaling in the presence or absence of amino acids.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37981208,

title = {Antisense oligonucleotides targeting the miR-29b binding site in the GRN mRNA increase progranulin translation},

author = {Geetika Aggarwal and Subhashis Banerjee and Spencer A Jones and Yousri Benchaar and Jasmine Bélanger and Myriam Sévigny and Denise M Smith and Michael L Niehoff and Monica Pavlack and Ian Mitchelle S de Vera and Terri L Petkau and Blair R Leavitt and Karen Ling and Paymaan Jafar-Nejad and Frank Rigo and John E Morley and Susan A Farr and Paul A Dutchak and Chantelle F Sephton and Andrew D Nguyen},

doi = {10.1016/j.jbc.2023.105475},

issn = {1083-351X},

year  = {2023},

date = {2023-12-01},

journal = {J Biol Chem},

volume = {299},

number = {12},

pages = {105475},

abstract = {Heterozygous GRN (progranulin) mutations cause frontotemporal dementia (FTD) due to haploinsufficiency, and increasing progranulin levels is a major therapeutic goal. Several microRNAs, including miR-29b, negatively regulate progranulin protein levels. Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but strategies for increasing target protein levels are limited. Here, we tested the efficacy of ASOs as enhancers of progranulin expression by sterically blocking the miR-29b binding site in the 3' UTR of the human GRN mRNA. We found 16 ASOs that increase progranulin protein in a dose-dependent manner in neuroglioma cells. A subset of these ASOs also increased progranulin protein in iPSC-derived neurons and in a humanized GRN mouse model. In FRET-based assays, the ASOs effectively competed for miR-29b from binding to the GRN 3' UTR RNA. The ASOs increased levels of newly synthesized progranulin protein by increasing its translation, as revealed by polysome profiling. Together, our results demonstrate that ASOs can be used to effectively increase target protein levels by partially blocking miR binding sites. This ASO strategy may be therapeutically feasible for progranulin-deficient FTD as well as other conditions of haploinsufficiency.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid37974279,

title = {Neuronal dysfunction caused by FUSR521G promotes ALS-associated phenotypes that are attenuated by NF-κB inhibition},

author = {Mari Carmen Pelaez and Antoine Desmeules and Pauline A Gelon and Bastien Glasson and Laetitia Marcadet and Alicia Rodgers and Daniel Phaneuf and Silvia Pozzi and Paul A Dutchak and Jean-Pierre Julien and Chantelle F Sephton},

doi = {10.1186/s40478-023-01671-1},

issn = {2051-5960},

year  = {2023},

date = {2023-11-01},

journal = {Acta Neuropathol Commun},

volume = {11},

number = {1},

pages = {182},

abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are related neurodegenerative diseases that belong to a common disease spectrum based on overlapping clinical, pathological and genetic evidence. Early pathological changes to the morphology and synapses of affected neuron populations in ALS/FTD suggest a common underlying mechanism of disease that requires further investigation. Fused in sarcoma (FUS) is a DNA/RNA-binding protein with known genetic and pathological links to ALS/FTD. Expression of ALS-linked FUS mutants in mice causes cognitive and motor defects, which correlate with loss of motor neuron dendritic branching and synapses, in addition to other pathological features of ALS/FTD. The role of ALS-linked FUS mutants in causing ALS/FTD-associated disease phenotypes is well established, but there are significant gaps in our understanding of the cell-autonomous role of FUS in promoting structural changes to motor neurons, and how these changes relate to disease progression. Here we generated a neuron-specific FUS-transgenic mouse model expressing the ALS-linked human FUSR521G variant, hFUS, to investigate the cell-autonomous role of FUSR521G in causing loss of dendritic branching and synapses of motor neurons, and to understand how these changes relate to ALS-associated phenotypes. Longitudinal analysis of mice revealed that cognitive impairments in juvenile hFUS mice coincide with reduced dendritic branching of cortical motor neurons in the absence of motor impairments or changes in the neuromorphology of spinal motor neurons. Motor impairments and dendritic attrition of spinal motor neurons developed later in aged hFUS mice, along with FUS cytoplasmic mislocalisation, mitochondrial abnormalities and glial activation. Neuroinflammation promotes neuronal dysfunction and drives disease progression in ALS/FTD. The therapeutic effects of inhibiting the pro-inflammatory nuclear factor kappa B (NF-κB) pathway with an analog of Withaferin A, IMS-088, were assessed in symptomatic hFUS mice and were found to improve cognitive and motor function, increase dendritic branches and synapses of motor neurons, and attenuate other ALS/FTD-associated pathological features. Treatment of primary cortical neurons expressing FUSR521G with IMS-088 promoted the restoration of dendritic mitochondrial numbers and mitochondrial activity to wild-type levels, suggesting that inhibition of NF-κB permits the restoration of mitochondrial stasis in our models. Collectively, this work demonstrates that FUSR521G has a cell-autonomous role in causing early pathological changes to dendritic and synaptic structures of motor neurons, and that these changes precede motor defects and other well-known pathological features of ALS/FTD. Finally, these findings provide further support that modulation of the NF-κB pathway in ALS/FTD is an important therapeutic approach to attenuate disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35151370,

title = {A postzygotic de novo NCDN mutation identified in a sporadic FTLD patient results in neurochondrin haploinsufficiency and altered FUS granule dynamics},

author = {Gaël Nicolas and Myriam Sévigny and François Lecoquierre and Florent Marguet and Andréanne Deschênes and Maria Carment Del Pelaez and Sébastien Feuillette and Anaïs Audebrand and Magalie Lecourtois and Stéphane Rousseau and Anne-Claire Richard and Kévin Cassinari and Vincent Deramecourt and Charles Duyckaerts and Anne Boland and Jean-François Deleuze and Vincent Meyer and Jordi Clarimon Echavarria and Ellen Gelpi and Haruhiko Akiyama and Masato Hasegawa and Ito Kawakami and Tsz H Wong and Jeroen G J Van Rooij and John C Van Swieten and Dominique Campion and Paul A Dutchak and David Wallon and Flavie Lavoie-Cardinal and Annie Laquerrière and Anne Rovelet-Lecrux and Chantelle F Sephton},

doi = {10.1186/s40478-022-01314-x},

issn = {2051-5960},

year  = {2022},

date = {2022-02-01},

journal = {Acta Neuropathol Commun},

volume = {10},

number = {1},

pages = {20},

abstract = {Frontotemporal dementia (FTD) is a heterogeneous clinical disorder characterized by progressive abnormalities in behavior, executive functions, personality, language and/or motricity. A neuropathological subtype of FTD, frontotemporal lobar degeneration (FTLD)-FET, is characterized by protein aggregates consisting of the RNA-binding protein fused in sarcoma (FUS). The cause of FTLD-FET is not well understood and there is a lack of genetic evidence to aid in the investigation of mechanisms of the disease. The goal of this study was to identify genetic variants contributing to FTLD-FET and to investigate their effects on FUS pathology. We performed whole-exome sequencing on a 50-year-old FTLD patient with ubiquitin and FUS-positive neuronal inclusions and unaffected parents, and identified a de novo postzygotic nonsense variant in the NCDN gene encoding Neurochondrin (NCDN), NM_014284.3:c.1206G > A, p.(Trp402*). The variant was associated with a ~ 31% reduction in full-length protein levels in the patient's brain, suggesting that this mutation leads to NCDN haploinsufficiency. We examined the effects of NCDN haploinsufficiency on FUS and found that depleting primary cortical neurons of NCDN causes a reduction in the total number of FUS-positive cytoplasmic granules. Moreover, we found that these granules were significantly larger and more highly enriched with FUS. We then examined the effects of a loss of FUS function on NCDN in neurons and found that depleting cells of FUS leads to a decrease in NCDN protein and mRNA levels. Our study identifies the NCDN protein as a likely contributor of FTLD-FET pathophysiology. Moreover, we provide evidence for a negative feedback loop of toxicity between NCDN and FUS, where loss of NCDN alters FUS cytoplasmic dynamics, which in turn has an impact on NCDN expression.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid36263379,

title = {Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease},

author = {Pauline A Gelon and Paul A Dutchak and Chantelle F Sephton},

doi = {10.3389/fnmol.2022.1000183},

issn = {1662-5099},

year  = {2022},

date = {2022-01-01},

journal = {Front Mol Neurosci},

volume = {15},

pages = {1000183},

abstract = {Synaptic loss is a pathological feature of all neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is a disease of the cortical and spinal motor neurons resulting in fatal paralysis due to denervation of muscles. FTD is a form of dementia that primarily affects brain regions controlling cognition, language and behavior. Once classified as two distinct diseases, ALS and FTD are now considered as part of a common disease spectrum based on overlapping clinical, pathological and genetic evidence. At the cellular level, aggregation of common proteins and overlapping gene susceptibilities are shared in both ALS and FTD. Despite the convergence of these two fields of research, the underlying disease mechanisms remain elusive. However, recent discovers from ALS and FTD patient studies and models of ALS/FTD strongly suggests that synaptic dysfunction is an early event in the disease process and a unifying hallmark of these diseases. This review provides a summary of the reported anatomical and cellular changes that occur in cortical and spinal motor neurons in ALS and FTD tissues and models of disease. We also highlight studies that identify changes in the proteome and transcriptome of ALS and FTD models and provide a conceptual overview of the processes that contribute to synaptic dysfunction in these diseases. Due to space limitations and the vast number of publications in the ALS and FTD fields, many articles have not been discussed in this review. As such, this review focuses on the three most common shared mutations in ALS and FTD, the hexanucleuotide repeat expansion within intron 1 of  9  (),  () and  (, with the intention of highlighting common pathways that promote synaptic dysfunction in the ALS-FTD disease spectrum.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35165201,

title = {NPRL2 Inhibition of mTORC1 Controls Sodium Channel Expression and Brain Amino Acid Homeostasis},

author = {Jeremy B Hui and Jose Cesar Hernandez Silva and Mari Carmen Pelaez and Myriam Sévigny and Janani Priya Venkatasubramani and Quentin Plumereau and Mohamed Chahine and Christophe D Proulx and Chantelle F Sephton and Paul A Dutchak},

doi = {10.1523/ENEURO.0317-21.2022},

issn = {2373-2822},

year  = {2022},

date = {2022-01-01},

journal = {eNeuro},

volume = {9},

number = {2},

abstract = {Genetic mutations in nitrogen permease regulator-like 2 (NPRL2) are associated with a wide spectrum of familial focal epilepsies, autism, and sudden unexpected death of epileptics (SUDEP), but the mechanisms by which NPRL2 contributes to these effects are not well known. NPRL2 is a requisite subunit of the GAP activity toward Rags 1 (GATOR1) complex, which functions as a negative regulator of mammalian target of rapamycin complex 1 (mTORC1) kinase when intracellular amino acids are low. Here, we show that loss of NPRL2 expression in mouse excitatory glutamatergic neurons causes seizures before death, consistent with SUDEP in humans with epilepsy. Additionally, the absence of NPRL2 expression increases mTORC1-dependent signal transduction and significantly alters amino acid homeostasis in the brain. Loss of NPRL2 reduces dendritic branching and increases the strength of electrically stimulated action potentials (APs) in neurons. The increased AP strength is consistent with elevated expression of epilepsy-linked, voltage-gated sodium channels in the NPRL2-deficient brain. Targeted deletion of NPRL2 in primary neurons increases the expression of sodium channel , whereas treatment with the pharmacological mTORC1 inhibitor called rapamycin prevents  upregulation. These studies demonstrate a novel role of NPRL2 and mTORC1 signaling in the regulation of sodium channels, which can contribute to seizures and early lethality.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33082139,

title = {FUS contributes to mTOR-dependent inhibition of translation},

author = {Myriam Sévigny and Isabelle Bourdeau Julien and Janani Priya Venkatasubramani and Jeremy B Hui and Paul A Dutchak and Chantelle F Sephton},

doi = {10.1074/jbc.RA120.013801},

issn = {1083-351X},

year  = {2020},

date = {2020-12-01},

journal = {J Biol Chem},

volume = {295},

number = {52},

pages = {18459--18473},

abstract = {The amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)-linked RNA-binding protein called FUS (sed in arcoma) has been implicated in several aspects of RNA regulation, including mRNA translation. The mechanism by which FUS affects the translation of polyribosomes has not been established. Here we show that FUS can associate with stalled polyribosomes and that this association is sensitive to mTOR (mammalian target of rapamycin) kinase activity. Specifically, we show that FUS association with polyribosomes is increased by Torin1 treatment or when cells are cultured in nutrient-deficient media, but not when cells are treated with rapamycin, the allosteric inhibitor of mTORC1. Moreover, we report that FUS is necessary for efficient stalling of translation because deficient cells are refractory to the inhibition of mTOR-dependent signaling by Torin1. We also show that ALS-linked FUS mutants R521G and P525L associate abundantly with polyribosomes and decrease global protein synthesis. Importantly, the inhibitory effect on translation by FUS is impaired by mutations that reduce its RNA-binding affinity. These findings demonstrate that FUS is an important RNA-binding protein that mediates translational repression through mTOR-dependent signaling and that ALS-linked FUS mutants can cause a toxic gain of function in the cytoplasm by repressing the translation of mRNA at polyribosomes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}