2002 — 2006 |
Trotti, Davide |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Impairment of Glial Glutamate Transporter Glt1 in Als @ Massachusetts General Hospital
DESCRIPTION (provided by applicant): The objective of this proposal is to study the molecular mechanisms leading to impairment and loss of the glial glutamate transporter GLT1 in amyotrophic lateral sclerosis (ALS). ALS is an age-dependent neurodegenerative disorder of motor neurons in the spinal cord, motor cortex and brain stem. There is a growing body of evidence indicating that deficient glutamate uptake may be a contributory factor to motor neuron loss in ALS. In ALS patients, a marked decrease in the maximal velocity of synaptosomal glutamate uptake was reported. The impairment was found in regions affected by the disease, such as the spinal cord and motor cortex and a specific reduction of GLT1 immunoreactivity (30-90 percent) in the motor cortex of 60 percent of sporadic ALS patients was reported. A marked loss of GLT1 immunoreactivity was also detected in transgenic mice expressing the SOD1(G85R) mutation, suggesting that the sporadic and the familial form of ALS (SOD component) share common molecular mechanisms. The precise events leading to GLT1 loss in ALS are not yet understood. The levels of GLT1 mRNA are unchanged, letting investigator suspect that the reduction of GLT1 is not due to decreased transcription of mRNA, but rather to some other events at the translation or post translational level. We have recently reported that intracellular delivery of H2O2 in cells expressing SOD mutations led to selective GLT1 inhibition. Moreover, we showed that the cytoplasmic C-terminal domain of GLT1 is involved in the inhibition. These observations provided the first link between the SOD1 mutations and GLT1 impairment in ALS. Why is GLT1 selectively damaged while other glutamate transporters are insensitive? GLT1 has the highest number of oxidant vulnerable amino acid residues, such as cysteines histidines and tyrosines and therefore is the most prone to oxidative modifications and damage. We expect that a damaged GLT1 caused by the SOD1 mutants would undergo to a sustained internalization and/or selective degradation. Little is known about glutamate transporters regulation and degradation and how their functional inhibition or stimulation affects the pathophysiological events of neurodegenerative diseases such as ALS. We plan to determine the pathways that lead to GLT1 loss in ALS by taking the following approaches: I) defining the molecular events responsible for the inactivation of GLT1 mediated by the SOD1 mutants and identifying the sites in the C-terminal domain of GLT1 that are targets for the inactivation; 2) defining the pathways of GLT1 degradation under normal conditions and under conditions initiated by the ALS-linked SOD1 mutations 3) using transgenic technology we will establish in vivo what role the inactivation of GLT1 is playing in the onset and progression of ALS.
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1 |
2003 |
Trotti, Davide |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Als Treatment With Gutamate Uptake Enhancers @ Massachusetts General Hospital
DESCRIPTION (provided by applicant): A considerable body of evidence implicates glutamate toxicity as a factor that contributes significantly to motor neuron injury, either as a primary or secondary event, in amyotrophic lateral sclerosis (ALS). Excitotoxicity has been suggested to be important in ALS, mediated by (a) increased glutamate levels that are a consequence of reduced glutamate uptake or (b) increased sensitivity to glutamate (e.g. altered glutamate receptors). Preventing excitotoxicity, for example by increasing the capacity of the cells to transport glutamate from the synaptic cleft, should be beneficial in ALS. We have developed a cell-based assay to screen for molecules that increase glutamate uptake. Using this assay, we recently screened a custom collection of 1,040 FDA-approved drugs and found eight positive hits that consistently augment glutamate uptake in vitro. We now propose to validate these eight effective drugs in a secondary screen in vivo in mice, and to test the hits in a mouse model of ALS as therapeutic candidates for the treatment of the disease. The study will be developed in the following aims: 1) Characterize the effect of the positive hits on the glutamate transport system in vivo. 2) Validate the positive hits in a secondary screen measuring glutamate uptake in synaptosomes from control mice after chronic treatment with the effective drugs. 3) Conduct a trial of the glutamate uptake enhancing compounds in SOD1-G93A transgenic mouse model of ALS. The ultimate goal of this project is to test the drugs effective in the mouse trail in a clinical trial for ALS patients.
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0.913 |
2004 |
Trotti, Davide |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Treatment With Gutamate Uptake Enhancers @ Massachusetts General Hospital
DESCRIPTION (provided by applicant): A considerable body of evidence implicates glutamate toxicity as a factor that contributes significantly to motor neuron injury, either as a primary or secondary event, in amyotrophic lateral sclerosis (ALS). Excitotoxicity has been suggested to be important in ALS, mediated by (a) increased glutamate levels that are a consequence of reduced glutamate uptake or (b) increased sensitivity to glutamate (e.g. altered glutamate receptors). Preventing excitotoxicity, for example by increasing the capacity of the cells to transport glutamate from the synaptic cleft, should be beneficial in ALS. We have developed a cell-based assay to screen for molecules that increase glutamate uptake. Using this assay, we recently screened a custom collection of 1,040 FDA-approved drugs and found eight positive hits that consistently augment glutamate uptake in vitro. We now propose to validate these eight effective drugs in a secondary screen in vivo in mice, and to test the hits in a mouse model of ALS as therapeutic candidates for the treatment of the disease. The study will be developed in the following aims: 1) Characterize the effect of the positive hits on the glutamate transport system in vivo. 2) Validate the positive hits in a secondary screen measuring glutamate uptake in synaptosomes from control mice after chronic treatment with the effective drugs. 3) Conduct a trial of the glutamate uptake enhancing compounds in SOD1-G93A transgenic mouse model of ALS. The ultimate goal of this project is to test the drugs effective in the mouse trail in a clinical trial for ALS patients.
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0.913 |
2009 — 2015 |
Trotti, Davide |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Impairment of the Glial Glutamate Transporter Glt1 in Als @ Thomas Jefferson University
DESCRIPTION (provided by applicant): Glia cells contribute to motor neuron degeneration and aggravate the progression of amyotrophic lateral sclerosis (ALS), an idiopathic, fatal neurodegenerative disease of the human motor system. The nature of this contribution is not yet fully defined. Deficient expression and activity of the astroglia glutamate transporter EAAT2 (a.k.a. GLT-1 in rodents) has been reported in ALS and the excitotoxicity resulting from the ensuing accumulation of glutamate is one conventional mechanism that could contribute to motor neuron degeneration. We unraveled an unconventional way for EAAT2 to trigger motor neuron toxicity. We showed that caspase-3 selectively cleaves EAAT2 in ALS, presumably through a mechanism that involves restricted non-apoptotic caspase-3 activation in astrocytes, generating a cytosolic EAAT2 C-terminus SUMOylated fragment (CTE- SUMO1). This fragment, when exogenously expressed in astrocytes, accumulates in their nuclei in PML- nuclear bodies and indirectly causes motor neuron toxicity via a mechanism that involves increased expression and release of netrin-1. Oligodendrocytes, not astrocytes, secrete netrin-1 in the normal adult CNS to maintain axonal homeostasis. Hence, an abnormal non-physiological release of netrin-1 from CTE-SUMO1+ astrocytes could be one non-cell autonomous mechanism of toxicity to motor neurons in vivo as well. We propose in this application to expand the relevance of our in vitro findings by testing in vivo the hypothesis of whether CTE-SUMO1 is responsible for motor neuron impairment and ALS-like phenotype. To restate our goal in terms of specific aims, we propose: (1) To determine whether CTE-SUMO1 is a mediator of motor neuron impairment in vivo and assess the modalities of toxicity; (2) To determine whether preventing the accumulation of CTE-SUMO1 subsides the ALS phenotype. Aim 1 involves selective expression of CTE-SUMO1in ventral horn astrocytes of adult mice to evaluate its possible toxic effects on the entire phrenic motor neuron pool targeted via intraspinal focal injections of an AAV1-CTE-SUMO1 viral construct at the C4-C6 cervical level. Aim 2 involves the creation of a novel knock-in SOD1-G93A mouse model in which the caspase-3 cleavage site in EAAT2 is mutated to prevent the endogenous production of CTE-SUMO1. In addition to these in vivo experiments, we propose: (3) To determine the disease-relevant effectors responsible for CTE-SUMO1 accumulation in astrocytes. We expect to unravel the modalities of CTE-SUMO1 generation in astrocytes and whether the presence of familial ALS-linked causative mutations catalyzes the process. It is a matter of importance to understand what effectors could lead to the cleavage of EAAT2 and therefore the ensuing CTE-SUMO1 creation. This knowledge can then be applied to design pharmacological approaches aiming at arresting CTE-SUMO1 production in ALS. The scope of this last aim could then be key, in particular if results of aim 1-2 establisha role of the astroglial CTE-SUMO1 fragment in motor neuron toxicity and ALS pathogenesis.
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1 |
2009 — 2012 |
Trotti, Davide |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mechanisms of Mutant Sod 1-Mediated Mitochondria Toxicity in the Spinal Cord of A @ Thomas Jefferson University
DESCRIPTION (provided by applicant): In the mutant SOD1-G93A (mutSOD1) mouse model of amyotrophic lateral sclerosis (ALS), the mutated form of SOD1 selectively binds and aggregates with Bcl-2 in spinal cord mitochondria. In this study we will test the hypothesis that the portion of mutSOD1 localized in spinal cord mitochondria must partner with Bcl-2 to manifest toxicity. We will also define the consequences of the mutSOD1/Bcl-2 aberrant binding on the spinal cord mitochondria ionic conductances and bioenergetics. By adapting and applying the patch-clamp electrophysiological technique (mito-attached configuration) to integral, neuronal and non-neuronal spinal cord mitochondria isolated from the double transgenic ALS mouse SOD1-93A: mitoCFP, we will systematically characterize the conductances of the outer mitochondrial membrane (OMM) throughout the different stages of disease, determining whether this mitochondria phenotype is specifically altered as the disease progresses. We are proposing three specific aims. In aim #1 we will study in vitro mutSOD1- mediated toxicity at the cellular and mitochondrial levels and its dependence on Bcl-2. In aim #2 we will study in situ the biophysical properties of neuronal and non-neuronal mitochondria isolated from the spinal cord of double transgenic SOD1-G93A: mitoCFP mice carrying fluorescently (cyan) tagged blue neuronal mitochondria. Furthermore, we will study the effect of mutSOD1 proteins on mitochondria outer membrane channels using mitochondria isolated from cells expressing Bcl-2 versus cells lacking Bcl-2 and transgenic mice. In aim #3 we will test in vivo the hypothesis that the binding of mutSOD1 to Bcl-2 is required for motor neuron toxicity and a determinant of the ALS phenotype by generating SOD1-G93A:Bcl-2(-/-) mice and comparing the disease phenotype of these mice to the SOD1-G93A mice in which Bcl-2 was not ablated. By developing these aims, we will understand whether by interacting with the anti-apoptotic protein Bcl-2, mutSOD1 leads to mitochondria dysfunction and the immediate relevance of this aberrant mechanism to motor neuron degeneration in ALS mice. PUBLIC HEALTH RELEVANCE Amyotrophic lateral sclerosis (ALS;a.k.a. Lou Gehrig's disease) is the most common adult motor neuron disease. The disease is characterized by the death of motor neurons in the spinal cord and motor cortex. This leads to spasticity, hyper-reflexia, general weakness and muscle atrophy. Failure of respiratory muscles is generally the fatal event, occurring within 1 - 5 years after the onset of the first symptoms. The overarching goal of this proposal is to shed light on the mechanisms of motor neuron death using transgenic mice model of ALS. The objective of our proposal is to study the disease mechanisms focusing on mitochondria of the spinal cord of these mice. Mitochondria are sub-cellular organelles and the main source of energy production in the body. They play a pivotal role in maintaining neuronal cell alive. A pathology-driven impairment of these organelles may shift the balance between life and death and lead to neuronal degeneration.
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1 |
2009 — 2010 |
Trotti, Davide |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
P-Glycoprotein Mediated Chemoresistance in Als Therapy @ Thomas Jefferson University
DESCRIPTION (provided by applicant): High expression levels, multispecificity, and high transport potency makes the P-glycoprotein a selective gatekeeper of the brain and blood-brain barrier and thus a primary obstacle to drug delivery in the CNS. As such, P-glycoprotein limits CNS entry of a large number of drugs and xenobiotics, contributes to the poor success rate of CNS drug candidates, and probably contributes to patient-to-patient variability in response to CNS pharmacotherapy. Modulating P-glycoprotein could therefore improve drug delivery into the CNS and drug therapy. Here, we propose to validate this concept in the context of ALS therapy. By following both genetic and pharmacologic approaches to obliterate the action of P-gp we will evaluate the therapeutic efficacy of nordihydroguaiaretic acid (NDGA) to the SOD1-G93A transgenic mouse model of ALS. We identified NDGA as a potent and specific glutamate transport activity enhancer in a cell-based screen for ALS;clinical testing in the SOD1-G93A mice indicated that its potential therapeutic efficacy could have been hampered by a disease-driven upregulation of P-gp transporters in the spinal cord. To further evaluate NDGA as candidate therapeutic we propose in Aim 1 to determine if genetic removal of P- glycoprotein-mediated pharmacoresistance will rescue NDGA-mediated glutamate uptake enhancing effect and therapeutic efficacy in a mouse model of ALS. In Aim 2 we will determine if co-treatment of the ALS mice with NDGA and elacridar, a potent and selective inhibitor of P-gp, will therapeutically benefit the mice. If successful, these approaches not only will determine the true impact on the ALS phenotype of increasing glutamate clearance in ALS mice, but will also provide the rationale to reconsider many unsuccessful clinical trials that have been attempted in the SOD1-G93A mouse model of ALS in which the function of multidrug transporter proteins could have compromised a possible positive outcome. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is one of the most devastating and lethal progressive neuromuscular disorders. Over 30,000 people are living with ALS in the United States and approximately 5,000 Americans will be diagnosed with ALS this year. P-glycoprotein limits the entry into the brain and spinal cord for a large number of drugs and contributes to the poor success rate of drug candidates. Modulating P-glycoprotein could therefore improve drug delivery into the brain and spinal cord. Here, we propose to validate this concept in the context of ALS therapy. By following both genetic and pharmacologic approaches to obliterate the action of P-glycoprotein we will evaluate the therapeutic value of a potent glutamate transport enhancer drug, NDGA, to mice model of ALS. If successful, this approach not only will determine the true therapeutic impact of increasing glutamate clearance in ALS mice, but also will open new therapeutic venues for ALS and provide the rationale to reconsider many unsuccessful clinical trials that have been attempted in mice models of ALS in which the function of P-gp could have hampered a possible positive outcome.
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1 |
2011 — 2015 |
Trotti, Davide |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Abc Efflux Transporters in Als @ Thomas Jefferson University
DESCRIPTION (provided by applicant): Limited drug penetration is an obstacle that is often encountered in the treatment of CNS diseases. One mechanism that may contribute to this phenomenon is the expression of ATP-binding cassette (ABC) drug efflux transporters (i.e. P-glycoprotein or P-gp, Multi-drug resistance proteins or MRPs, breast cancer resistance protein or BCRP, a.k.a. ABCG2) at the blood brain barrier (BBB) and blood cerebrospinal fluid (BCSF) barrier. ABC transporters also localize to a lesser extent at the CNS parenchyma cells where they act as secondary barrier to neural penetration of substances. Efflux transporters also extrude catabolites and toxins to prevent their harmful accumulation in the cell, constituting the major mechanism of cell adaptation to disease-mediated and environmental stress. Little is known on ABC transporters localization and regulation in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease of the motor system. Our preliminary data show increased P-gp expression in spinal cord astrocytes of the SOD1-G93A mouse model of ALS as well as in spinal cord specimen homogenates of sporadic and familial ALS patients. From a therapeutic perspective, this suggests that the obstacle to drug penetration in the CNS is increased by the disease and must be overcome to develop effective pharmacotherapies for ALS. Given their multi-specificity, the recognition of efflux transporters as critical players in CNS diseases is unquestioned although important questions remain unanswered. For example: How does ALS affect efflux transporters localization and function? Which ALS-specific signaling pathways are responsible for up-regulation in P-gp? Will ALS-mediated up-regulation in P-gp and/or other ABC transporters change how we therapeutically treat the mouse model of the disease, and ultimately ALS patients? To fill this gap in knowledge, we propose: (1) To investigate activity, expression and distribution profile of P- gp and other relevant ABC drug transporters in ALS; (2) To study whether efflux transporter activity in non- neuronal cells contributes to motor neuron degeneration in in-vitro and in-vivo models of ALS; (3) To investigate the impact of eliminating ABC transporter function on ALS therapeutics. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is one of the most devastating and lethal progressive neuromuscular disorders, affecting motor neurons in the spinal cord and motor cortex. Over 30,000 people are living with this disease in the United States and approximately 5,000 Americans will be diagnosed with ALS this year. Multidrug efflux ABC transporters limit the entry into the brain and spinal cord of a large number of drugs, contributing to the poor success rate of promising drug candidates, and regulate the extrusion of a variety of substances, including catabolites and potential toxic molecules that could be harmful to cells. Modulating the activity and expression pattern of these transporters could therefore improve drug delivery into the brain and spinal cord and affect the overall cellular homeostasis. In this application we propose to study the regulation and role of these ABC transporters in ALS. Our ultimate goal is to understand the pathogenic mechanisms of ALS to improve the chances of success of pharmacotherapy for this disease.
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1 |
2014 — 2015 |
Trotti, Davide |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Development of a Mouse Model of C9orf72 Als/Ftd Expressing Ran Translated Peptide @ Thomas Jefferson University
? DESCRIPTION (provided by applicant): Research on ALS has recently been the subject of major advances. Two independent groups have identified an expansion of GGGGCC repeats in the non-coding region of the first intron of the C9ORF72 gene as the most common genetic cause of amyotrophic lateral sclerosis (ALS) and FTD (frontotemporal dementia) identified to date. Accumulation of RNA transcripts containing GGGGCC (sense) or CCCCGG (antisense) repeats were found to aggregate in nuclear foci in frontal cortex and spinal cord in C9ORF72 ALS/FTLD patients. Recently, toxicity of dipeptide repeat products (DPRs) generated via repeat associated non-ATG (RAN) translation of GGGGCC or CCCCGG repeat expansions has been proposed as potential pathogenic mechanism in C9- ALS/FTD, and DPR aggregates have been detected in affected and non-affected regions in ALS and ALS/FTD patients. RAN translation from sense and anti-sense directions has been reported in several nucleotide repeat disorders, including C9-ALS/FTD, making RAN translation an established occurrence in these expansion disorders, and also implicating a pathogenic role for RAN translated proteins. We established cellular models of C9-ALS/FTD using primary motor and cortical neurons, which are known to degenerate in ALS/FTD. By expressing fluorescently tagged homopolymeric C9RAN proteins (or DPRs) we were able to decipher their respective impact on neuronal viability using longitudinal time-lapse live-cell imaging, transgenic Drosophila models and found that Proline-Arginine dipeptides (PR) are robustly neurotoxic when expressed in vitro and in vivo. As next step in our investigation, we propose here to generate transgenic mice that express PR dipeptide repeats. Our hypothesis is that expression of PR aggregates in disease-relevant neuronal populations in mice will result in development of key phenotypes and pathologies that resemble those in ALS/FTD patients. This hypothesis is formulated based on extensive evidence of gained toxicity of PR aggregates in neuronal cell culture models as well as eye degeneration and lethality phenotypes when PR proteins are expressed in Drosophila eye and motor neurons. The rationale of the proposed research is that, once the model is fully characterized, it will have the potential to become a vital tool to unravel the basic mechanisms behind neurodegenerative processes in C9-ALS/FTD and, ultimately, for development of therapeutic interventions.
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1 |
2018 |
Trotti, Davide Yang, Yongjie (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Exosome-Mediated Propagation of Disease Linked Poly-Dipeptides in C9orf72-Ftd/Als @ Thomas Jefferson University
A growing body of evidence uncovered a propensity for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) pathogenic proteins to propagate from cell-to-cell. Although few other mechanisms have been proposed, secretion of exosomes has been reported to occur from different neural cell types, including neurons, and to potentially serve as a new intercellular communication route within the CNS. Interestingly, based on the evidence of focality and neuroanatomical propagation of clinical symptoms, it was also hypothesized that the cerebro-spinal fluid (CSF) could serve as vehicle for pathogenic proteins spread, at least in ALS. Utilizing different in vitro cell culture platforms, including spinal motor neurons derived from iPSCs of C9orf72 patients, we recently learnt that C9orf72-linked dipeptide proteins (DPRs) spread between neural cells via the exosome-dependent pathway. By analyzing a newly generated exosome-reporter transgenic mouse, we also found that exosomes are capable of migrating extensive distance in vivo. These observations led us to postulate that an exosome-mediated propagation of DPRs could be a modality by which toxic insults spread in disease-afflicted CNS areas in C9orf72-FTD/ALS. We will be testing using complementary in vitro and in vivo approaches the novel hypothesis that transmitted DPRs transfer injury via exosomes to both neighboring cells, but also to neurons downstream in synaptic circuits. We propose: (1) To investigate exosome-mediated mechanisms of DPRs transmission in CNS cells; (2) To examine the modalities of cell-to-cell propagation of DPRs in vivo; (3) To examine whether cell transfer of DPRs propagates toxicity. The proposed work has the potential to open up an entirely new field of C9orf72 FTD/ALS research, at the same time, providing important clues to the fundamental biological processes in brain cellular communications relevant to brain diseases. Thus, the results are expected to have a significant impact for understanding C9orf72-linked FTD/ALS pathogenesis and eventually treating patients.
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1 |
2018 — 2019 |
Hou, Ya-Ming Trotti, Davide |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Tractable Models For C9orf72-Linked Ran Translation in Als/Ftd @ Thomas Jefferson University
An hexa-nucleotide GGGGCC repeat expansion (HRE) was identified as the most common genetic cause of C9orf72-linked amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Both sense and antisense HRE strands of C9orf72 are translated by a repeat associated non-canonical AUG translation (RANT) mechanism in mutation carriers, resulting in the production of neurotoxic dipeptide- repeat proteins (DPRs). The mechanism and dynamics of RANT are largely unknown. For example, is RANT occurring only in disease-degenerating cells (e.g. cortical and motor neurons) versus other non- degenerating cell types (e.g., glia cells)? What are the molecular and cellular signals that initiate RANT? We hypothesize that the most important component for translation, canonical or non-canonical, is the choice for tRNA to read a specific codon to control the speed and quality of translation in specific cells and location. The critical barrier to answer these questions and to make progress in the field is the lack of experimental tractable models in disease?relevant cells. Here we propose: 1. To develop C9-ALS/FTD relevant cell-based models, using primary neurons and astrocytes as experimental platforms to study cell-specificity and molecular trigger of RANT driven by the C9orf72 HRE; 2. To develop a cell-free model system using brain ribosomes and tRNA pools to study the tRNA requirements for RANT driven by the C9orf72 HRE. These models will exploit distinct yet complementary aspects of C9orf72-linked RANT (herein referred as C9-RANT). A number of important questions will be addressed using these models: (i) Is the production of certain DPRs dependent on cell types? (ii) Do cellular stressors trigger or increase C9-RANT? (iii) Which tRNA isodecoders are used to read the Pro, Arg, Ala, Gly codons by RANT? The answers will define the basic parameters of C9-RANT and its pathogenic implication for C9-ALS/FTD. We believe we have unique and complementary expertise to successfully address these questions, which are not to the best of our knowledge being pursued elsewhere.
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1 |