144 results on '"Bonini NM"'
Search Results
2. Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models.
- Author
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Finkbeiner, Steven, Kim, H-J, Raphael, AR, LaDow, ES, McGurk, L, Weber, RA, Trojanowski, JQ, Lee, VM-Y, Gitler, AD, and Bonini, NM
- Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal, late-onset neurodegenerative disease primarily affecting motor neurons. A unifying feature of many proteins associated with ALS, including TDP-43 and ataxin-2, is that they localize to stress granules. Unexpe
- Published
- 2014
3. Evaluating the prevalence of polyglutamine repeat expansions in amyotrophic lateral sclerosis.
- Author
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Lee T, Li YR, Chesi A, Hart MP, Ramos D, Jethava N, Hosangadi D, Epstein J, Hodges B, Bonini NM, Gitler AD, Lee, T, Li, Y R, Chesi, A, Hart, M P, Ramos, D, Jethava, N, Hosangadi, D, Epstein, J, and Hodges, B
- Published
- 2011
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4. Biochemical and pathological characterization of Lrrk2.
- Author
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Giasson BI, Covy JP, Bonini NM, Hurtig HI, Farrer MJ, Trojanowski JQ, and Van Deerlin VM
- Published
- 2006
5. Author Correction: Senescent glia link mitochondrial dysfunction and lipid accumulation.
- Author
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Byrns CN, Perlegos AE, Miller KN, Jin Z, Carranza FR, Manchandra P, Beveridge CH, Randolph CE, Chaluvadi VS, Zhang SL, Srinivasan AR, Bennett FC, Sehgal A, Adams PD, Chopra G, and Bonini NM
- Published
- 2024
- Full Text
- View/download PDF
6. Senescent glia link mitochondrial dysfunction and lipid accumulation.
- Author
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Byrns CN, Perlegos AE, Miller KN, Jin Z, Carranza FR, Manchandra P, Beveridge CH, Randolph CE, Chaluvadi VS, Zhang SL, Srinivasan AR, Bennett FC, Sehgal A, Adams PD, Chopra G, and Bonini NM
- Subjects
- Animals, Female, Humans, Male, Fibroblasts metabolism, Fibroblasts pathology, Longevity, Neurons metabolism, Neurons pathology, Oxidative Stress, Transcription Factor AP-1 metabolism, Lipids, Inflammation metabolism, Inflammation pathology, Aging metabolism, Aging pathology, Brain metabolism, Brain pathology, Brain cytology, Cellular Senescence, Drosophila melanogaster metabolism, Drosophila melanogaster cytology, Lipid Metabolism, Mitochondria metabolism, Mitochondria pathology, Neuroglia metabolism, Neuroglia pathology
- Abstract
Senescence is a cellular state linked to ageing and age-onset disease across many mammalian species
1,2 . Acutely, senescent cells promote wound healing3,4 and prevent tumour formation5 ; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. Whereas senescent cells are active targets for anti-ageing therapy6-11 , why these cells form in vivo, how they affect tissue ageing and the effect of their elimination remain unclear12,13 . Here we identify naturally occurring senescent glia in ageing Drosophila brains and decipher their origin and influence. Using Activator protein 1 (AP1) activity to screen for senescence14,15 , we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly lifespan and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally occurring senescent glia in vivo and indicate that these cells link key ageing phenomena: mitochondrial dysfunction and lipid accumulation., (© 2024. The Author(s).)- Published
- 2024
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7. Cell type-specific regulation of m 6 A modified RNAs in the aging Drosophila brain.
- Author
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Perlegos AE, Byrns CN, and Bonini NM
- Subjects
- Animals, Neurons metabolism, Aging genetics, RNA metabolism, Drosophila genetics, Brain metabolism
- Abstract
The aging brain is highly vulnerable to cellular stress, and neurons employ numerous mechanisms to combat neurotoxic proteins and promote healthy brain aging. The RNA modification m
6 A is highly enriched in the Drosophila brain and is critical for the acute heat stress response of the brain. Here we examine m6 A in the fly brain with the chronic stresses of aging and degenerative disease. m6 A levels dynamically increased with both age and disease in the brain, marking integral neuronal identity and signaling pathway transcripts that decline in level with age and disease. Unexpectedly, there is opposing impact of m6 A transcripts in neurons versus glia, which conferred different outcomes on animal health span upon Mettl3 knockdown to reduce m6 A: whereas Mettl3 function is normally beneficial to neurons, it is deleterious to glia. Moreover, knockdown of Mettl3 in glial tauopathy reduced tau pathology and increased animal survival. These findings provide mechanistic insight into regulation of m6 A modified transcripts with age and disease, highlighting an overall beneficial function of Mettl3 in neurons in response to chronic stresses, versus a deleterious impact in glia., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)- Published
- 2024
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8. TDP-43 impairs sleep in Drosophila through Ataxin-2 -dependent metabolic disturbance.
- Author
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Perlegos AE, Durkin J, Belfer SJ, Rodriguez A, Shcherbakova O, Park K, Luong J, Bonini NM, and Kayser MS
- Subjects
- Animals, Humans, Ataxin-2, DNA-Binding Proteins genetics, Drosophila, Amyotrophic Lateral Sclerosis, Neurodegenerative Diseases
- Abstract
Neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia are associated with substantial sleep disruption, which may accelerate cognitive decline and brain degeneration. Here, we define a role for trans-activation response element (TAR) DNA binding protein 43 (TDP-43), a protein associated with human neurodegenerative disease, in regulating sleep using Drosophila . Expression of TDP-43 severely disrupts sleep, and the sleep deficit is rescued by Atx2 knockdown. Brain RNA sequencing revealed that Atx2 RNA interference regulates transcripts enriched for small-molecule metabolic signaling in TDP-43 brains. Focusing on these Atx2 -regulated genes, we identified suppressors of the TDP-43 sleep phenotype enriched for metabolism pathways. Knockdown of Atx2 or treatment with rapamycin attenuated the sleep phenotype and mitigated the disruption of small-molecule glycogen metabolism caused by TDP-43. Our findings provide a connection between toxicity of TDP-43 and sleep disturbances and highlight key aspects of metabolism that interplay with TDP-43 toxicity upon Atx2 rescue.
- Published
- 2024
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9. Publisher Correction: m 1 A in CAG repeat RNA binds to TDP-43 and induces neurodegeneration.
- Author
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Sun Y, Dai H, Dai X, Yin J, Cui Y, Liu X, Gonzalez G, Yuan J, Tang F, Wang N, Perlegos AE, Bonini NM, Yang XW, Gu W, and Wang Y
- Published
- 2024
- Full Text
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10. dTrmt10A impacts Hsp70 chaperone m 6 A levels and the stress response in the Drosophila brain.
- Author
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Perlegos AE, Quan X, Donnelly KM, Shen H, Shields EJ, Elashal H, Fange Liu K, and Bonini NM
- Subjects
- Animals, Humans, Molecular Chaperones metabolism, Methyltransferases genetics, Methyltransferases metabolism, Brain metabolism, RNA, Drosophila genetics, HSP70 Heat-Shock Proteins genetics, HSP70 Heat-Shock Proteins metabolism
- Abstract
Chronic cellular stress has a profound impact on the brain, leading to degeneration and accelerated aging. Recent work has revealed the vital role of RNA modifications, and the proteins responsible for regulating them, in the stress response. In our study, we defined the role of CG14618/dTrmt10A, the Drosophila counterpart of human TRMT10A a N
1 -methylguanosine methyltransferase, on m6 A regulation and heat stress resilience in the Drosophila brain. By m6 A-IP RNA sequencing on Drosophila head tissue, we demonstrated that manipulating dTrmt10A levels indirectly regulates m6 A levels on polyA + RNA. dTrmt10A exerted its influence on m6 A levels on transcripts enriched for neuronal signaling and heat stress pathways, similar to the m6 A methyltransferase Mettl3. Intriguingly, its impact primarily targeted 3' UTR m6 A, setting it apart from the majority of Drosophila m6 A-modified transcripts which display 5' UTR enrichment. Upregulation of dTrmt10A led to increased resilience to acute heat stress, decreased m6 A modification on heat shock chaperones, and coincided with decreased decay of chaperone transcripts and increased translation of chaperone proteins. Overall, these findings establish a potential mechanism by which dTrmt10A regulates the acute brain stress response through m6 A modification., (© 2023. The Author(s).)- Published
- 2023
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11. m 1 A in CAG repeat RNA binds to TDP-43 and induces neurodegeneration.
- Author
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Sun Y, Dai H, Dai X, Yin J, Cui Y, Liu X, Gonzalez G, Yuan J, Tang F, Wang N, Perlegos AE, Bonini NM, Yang XW, Gu W, and Wang Y
- Subjects
- Animals, Humans, Cytoplasm metabolism, Disease Models, Animal, Adenosine analogs & derivatives, Adenosine metabolism, Caenorhabditis elegans genetics, Caenorhabditis elegans metabolism, DNA-Binding Proteins metabolism, Drosophila melanogaster genetics, Drosophila melanogaster metabolism, Neurodegenerative Diseases genetics, Neurodegenerative Diseases metabolism, Neurodegenerative Diseases pathology, RNA chemistry, RNA genetics, RNA metabolism, Trinucleotide Repeat Expansion genetics
- Abstract
Microsatellite repeat expansions within genes contribute to a number of neurological diseases
1,2 . The accumulation of toxic proteins and RNA molecules with repetitive sequences, and/or sequestration of RNA-binding proteins by RNA molecules containing expanded repeats are thought to be important contributors to disease aetiology3-9 . Here we reveal that the adenosine in CAG repeat RNA can be methylated to N1 -methyladenosine (m1 A) by TRMT61A, and that m1 A can be demethylated by ALKBH3. We also observed that the m1 A/adenosine ratio in CAG repeat RNA increases with repeat length, which is attributed to diminished expression of ALKBH3 elicited by the repeat RNA. Additionally, TDP-43 binds directly and strongly with m1 A in RNA, which stimulates the cytoplasmic mis-localization and formation of gel-like aggregates of TDP-43, resembling the observations made for the protein in neurological diseases. Moreover, m1 A in CAG repeat RNA contributes to CAG repeat expansion-induced neurodegeneration in Caenorhabditis elegans and Drosophila. In sum, our study offers a new paradigm of the mechanism through which nucleotide repeat expansion contributes to neurological diseases and reveals a novel pathological function of m1 A in RNA. These findings may provide an important mechanistic basis for therapeutic intervention in neurodegenerative diseases emanating from CAG repeat expansion., (© 2023. The Author(s).)- Published
- 2023
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12. Author Correction: Toxic expanded GGGGCC repeat transcription is mediated by the PAF1 complex in C9orf72-associated FTD.
- Author
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Goodman LD, Prudencio M, Kramer NJ, Martinez-Ramirez LF, Srinivasan AR, Lan M, Parisi MJ, Zhu Y, Chew J, Cook CN, Berson A, Gitler AD, Petrucelli L, and Bonini NM
- Published
- 2023
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13. A perspective on Drosophila genetics and its insight into human neurodegenerative disease.
- Author
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Bonini NM
- Abstract
Drosophila has been long appreciated as a classic genetic system for its ability to define gene function in vivo . Within the last several decades, the fly has also emerged as a premiere system for modeling and defining mechanisms of human disease by expressing dominant human disease genes and analyzing the effects. Here I discuss key aspects of this latter approach that first intrigued me to focus my laboratory research on this idea. Differences between the loss-of-function vs. the gain-of-function approach are raised-and the insight of these approaches for appreciating mechanisms that contribute to human neurodegenerative disease. The application of modifier genetics, which is a prominent goal of models of human disease, has implications for how specific genes or pathways intersect with the dominant disease-associated mechanisms. Models of human disease will continue to reveal unanticipated insight into fundamental cellular processes-insight that might be harder to glean from classical genetic methodologies vs modifier genetics of disease., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bonini.)
- Published
- 2022
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14. Mettl3-dependent m 6 A modification attenuates the brain stress response in Drosophila.
- Author
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Perlegos AE, Shields EJ, Shen H, Liu KF, and Bonini NM
- Subjects
- Animals, Brain metabolism, Methylation, RNA, Messenger metabolism, Adenosine metabolism, Drosophila genetics, Drosophila metabolism
- Abstract
N
6 -methyladenosine (m6 A), the most prevalent internal modification on eukaryotic mRNA, plays an essential role in various stress responses. The brain is uniquely vulnerable to cellular stress, thus defining how m6 A sculpts the brain's susceptibility may provide insight to brain aging and disease-related stress. Here we investigate the impact of m6 A mRNA methylation in the adult Drosophila brain with stress. We show that m6 A is enriched in the adult brain and increases with heat stress. Through m6 A-immunoprecipitation sequencing, we show 5'UTR Mettl3-dependent m6 A is enriched in transcripts of neuronal processes and signaling pathways that increase upon stress. Mettl3 knockdown results in increased levels of m6 A targets and confers resilience to stress. We find loss of Mettl3 results in decreased levels of nuclear m6 A reader Ythdc1, and knockdown of Ythdc1 also leads to stress resilience. Overall, our data suggest that m6 A modification in Drosophila dampens the brain's biological response to stress., (© 2022. The Author(s).)- Published
- 2022
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15. Loss of miR-34 in Drosophila dysregulates protein translation and protein turnover in the aging brain.
- Author
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Srinivasan AR, Tran TT, and Bonini NM
- Subjects
- 3' Untranslated Regions genetics, Aging genetics, Aging metabolism, Animals, Brain metabolism, Drosophila genetics, Drosophila melanogaster metabolism, Histones metabolism, Protein Biosynthesis, Drosophila Proteins genetics, Drosophila Proteins metabolism, MicroRNAs genetics, MicroRNAs metabolism, Neurodegenerative Diseases metabolism
- Abstract
Aging is a risk factor for neurodegenerative disease, but precise mechanisms that influence this relationship are still under investigation. Work in Drosophila melanogaster identified the microRNA miR-34 as a modifier of aging and neurodegeneration in the brain. MiR-34 mutants present aspects of early aging, including reduced lifespan, neurodegeneration, and a buildup of the repressive histone mark H3K27me3. To better understand how miR-34 regulated pathways contribute to age-associated phenotypes in the brain, here we transcriptionally profiled the miR-34 mutant brain. This identified that genes associated with translation are dysregulated in the miR-34 mutant. The brains of these animals show increased translation activity, accumulation of protein aggregation markers, and altered autophagy activity. To determine if altered H3K27me3 was responsible for this proteostasis dysregulation, we studied the effects of increased H3K27me3 by mutating the histone demethylase Utx. Reduced Utx activity enhanced neurodegeneration and mimicked the protein accumulation seen in miR-34 mutant brains. However, unlike the miR-34 mutant, Utx mutant brains did not show similar altered autophagy or translation activity, suggesting that additional miR-34-targeted pathways are involved. Transcriptional analysis of predicted miR-34 targets identified Lst8, a subunit of Tor Complex 1 (TORC1), as a potential target. We confirmed that miR-34 regulates the 3' UTR of Lst8 and identified several additional predicted miR-34 targets that may be critical for maintaining proteostasis and brain health. Together, these results present novel understanding of the brain and the role of the conserved miRNA miR-34 in impacting proteostasis in the brain with age., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
- Published
- 2022
- Full Text
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16. Toxicity of pathogenic ataxin-2 in Drosophila shows dependence on a pure CAG repeat sequence.
- Author
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McGurk L, Rifai OM, Shcherbakova O, Perlegos AE, Byrns CN, Carranza FR, Zhou HW, Kim HJ, Zhu Y, and Bonini NM
- Subjects
- Animals, Ataxin-3 genetics, Ataxins genetics, Drosophila genetics, Trinucleotide Repeat Expansion genetics, Disease Models, Animal, Amyotrophic Lateral Sclerosis genetics, Ataxin-2 genetics, Spinocerebellar Ataxias genetics
- Abstract
Spinocerebellar ataxia type 2 is a polyglutamine (polyQ) disease associated with an expanded polyQ domain within the protein product of the ATXN2 gene. Interestingly, polyQ repeat expansions in ATXN2 are also associated with amyotrophic lateral sclerosis (ALS) and parkinsonism depending upon the length of the polyQ repeat expansion. The sequence encoding the polyQ repeat also varies with disease presentation: a pure CAG repeat is associated with SCA2, whereas the CAG repeat in ALS and parkinsonism is typically interrupted with the glutamine encoding CAA codon. Here, we asked if the purity of the CAG sequence encoding the polyQ repeat in ATXN2 could impact the toxicity of the ataxin-2 protein in vivo in Drosophila. We found that ataxin-2 encoded by a pure CAG repeat conferred toxicity in the retina and nervous system, whereas ataxin-2 encoded by a CAA-interrupted repeat or CAA-only repeat failed to confer toxicity, despite expression of the protein at similar levels. Furthermore, the CAG-encoded ataxin-2 protein aggregated in the fly eye, while ataxin-2 encoded by either a CAA/G or CAA repeat remained diffuse. The toxicity of the CAG-encoded ataxin-2 protein was also sensitive to the translation factor eIF4H, a known modifier of the toxic GGGGCC repeat in flies. These data indicate that ataxin-2 encoded by a pure CAG versus interrupted CAA/G polyQ repeat domain is associated with differential toxicity, indicating that mechanisms associated with the purity of the sequence of the polyQ domain contribute to disease., (© The Author(s) 2021. Published by Oxford University Press.)
- Published
- 2021
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17. Synergistic effects of brain injury and aging: common mechanisms of proteostatic dysfunction.
- Author
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Saikumar J and Bonini NM
- Subjects
- Aging, Animals, Brain, Humans, Brain Injuries, Neurodegenerative Diseases
- Abstract
The aftermath of TBI is associated with an acute stress response and the accumulation of insoluble protein aggregates. Even after the symptoms of TBI are resolved, insidious molecular processes continue to develop, which often ultimately result in the development of age-associated neurodegenerative disorders. The precise molecular cascades that drive unhealthy brain aging are still largely unknown. In this review, we discuss proteostatic dysfunction as a converging mechanism contributing to accelerated brain aging after TBI. We examine evidence from human tissue and in vivo animal models, spanning both the aging and injury contexts. We conclude that TBI has a sustained debilitating effect on the proteostatic machinery, which may contribute to the accelerated pathological and cognitive hallmarks of aging that are observed following injury., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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18. Glial AP1 is activated with aging and accelerated by traumatic brain injury.
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Byrns CN, Saikumar J, and Bonini NM
- Subjects
- Animals, Humans, Brain pathology, Drosophila genetics, Drosophila metabolism, Microglia pathology, Neuroglia pathology, Aging genetics, Brain Injuries, Traumatic pathology, Transcription Factor AP-1 genetics, Transcription Factor AP-1 metabolism
- Abstract
The emergence of degenerative disease after traumatic brain injury is often described as an acceleration of normal age-related processes. Whether similar molecular processes occur after injury and in age is unclear. Here we identify a functionally dynamic and lasting transcriptional response in glia, mediated by the conserved transcription factor AP1. In the early post-TBI period, glial AP1 is essential for recovery, ensuring brain integrity and animal survival. In sharp contrast, chronic AP1 activation promotes human tau pathology, tissue loss, and mortality. We show a similar process activates in healthy fly brains with age. In humans, AP1 activity is detected after moderate TBI and correlates with microglial activation and tau pathology. Our data provide key molecular insight into glia, highlighting that the same molecular process drives dynamic and contradictory glia behavior in TBI, and possibly age, first acting to protect but chronically promoting disease., Competing Interests: Declaration of Interests: The authors declare no competing interests.
- Published
- 2021
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19. An Integrated Multi-omics Approach Identifies Therapeutic Potential for ATP6V1A in Late Onset Alzheimer's Disease.
- Author
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Byrns CN and Bonini NM
- Subjects
- Gene Regulatory Networks, Humans, Alzheimer Disease drug therapy, Alzheimer Disease genetics, Vacuolar Proton-Translocating ATPases
- Abstract
In this issue of Neuron, Wang et al. employ an impressive multi-omics approach, including gene co-expression network analyses and drug repositioning, to normalize disease-disrupted gene modules and identify a therapeutically relevant driver of Alzheimer's disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)
- Published
- 2021
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20. Inducing different severities of traumatic brain injury in Drosophila using a piezoelectric actuator.
- Author
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Saikumar J, Kim J, Byrns CN, Hemphill M, Meaney DF, and Bonini NM
- Subjects
- Animals, Brain pathology, Brain Injuries, Traumatic etiology, Female, Head pathology, Humans, Male, Brain Injuries, Traumatic pathology, Disease Models, Animal, Drosophila melanogaster physiology
- Abstract
Drosophila models have been instrumental in providing insights into molecular mechanisms of neurodegeneration, with wide application to human disease. The brain degeneration associated with traumatic brain injury (TBI) has been modeled in Drosophila using devices that inflict trauma on multiple parts of the fly body, including the head. However, the injuries produced by these models are not specific in location and are inconsistent between individual animals. We have recently developed a device that can be used to inflict controlled head injury to flies, resulting in physiological responses that are remarkably similar to those observed in humans with TBI. This protocol describes the construction, calibration and use of the Drosophila TBI (dTBI) device, a platform that employs a piezoelectric actuator to reproducibly deliver a force in order to briefly compress the fly head against a metal surface. The extent of head compression can be controlled through an electrical circuit, allowing the operator to set different levels of injury. The entire device can be assembled and calibrated in under a week. The device components and the necessary electrical tools are readily available and cost ~$800. The dTBI device can be used to harness the power of Drosophila genetics and perform large-scale genetic or pharmacological screens, using a 7-d post-injury survival curve to identify modifiers of injury.
- Published
- 2021
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21. Author Correction: An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer's disease.
- Author
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Nativio R, Lan Y, Donahue G, Sidoli S, Berson A, Srinivasan AR, Shcherbakova O, Amlie-Wolf A, Nie J, Cui X, He C, Wang LS, Garcia BA, Trojanowski JQ, Bonini NM, and Berger SL
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
- Full Text
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22. An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer's disease.
- Author
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Nativio R, Lan Y, Donahue G, Sidoli S, Berson A, Srinivasan AR, Shcherbakova O, Amlie-Wolf A, Nie J, Cui X, He C, Wang LS, Garcia BA, Trojanowski JQ, Bonini NM, and Berger SL
- Subjects
- Acetylation, Alzheimer Disease pathology, Amyloid beta-Peptides genetics, Chromatin genetics, Epigenome genetics, Histone Acetyltransferases genetics, Histone Code genetics, Histones genetics, Humans, Peptide Fragments genetics, Protein Aggregation, Pathological pathology, Signal Transduction genetics, Transcriptional Activation genetics, Alzheimer Disease genetics, Protein Aggregation, Pathological genetics, Proteome genetics, Transcriptome genetics
- Abstract
Protein aggregation is the hallmark of neurodegeneration, but the molecular mechanisms underlying late-onset Alzheimer's disease (AD) are unclear. Here we integrated transcriptomic, proteomic and epigenomic analyses of postmortem human brains to identify molecular pathways involved in AD. RNA sequencing analysis revealed upregulation of transcription- and chromatin-related genes, including the histone acetyltransferases for H3K27ac and H3K9ac. An unbiased proteomic screening singled out H3K27ac and H3K9ac as the main enrichments specific to AD. In turn, epigenomic profiling revealed gains in the histone H3 modifications H3K27ac and H3K9ac linked to transcription, chromatin and disease pathways in AD. Increasing genome-wide H3K27ac and H3K9ac in a fly model of AD exacerbated amyloid-β42-driven neurodegeneration. Together, these findings suggest that AD involves a reconfiguration of the epigenome, wherein H3K27ac and H3K9ac affect disease pathways by dysregulating transcription- and chromatin-gene feedback loops. The identification of this process highlights potential epigenetic strategies for early-stage disease treatment.
- Published
- 2020
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23. Dynamic neural and glial responses of a head-specific model for traumatic brain injury in Drosophila .
- Author
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Saikumar J, Byrns CN, Hemphill M, Meaney DF, and Bonini NM
- Subjects
- Animals, Behavior, Animal, Brain Injuries, Traumatic diagnostic imaging, Brain Injuries, Traumatic pathology, Disease Models, Animal, Head, Humans, Male, Neurodegenerative Diseases metabolism, Neuroglia pathology, Stress, Physiological, Brain metabolism, Brain Injuries, Traumatic metabolism, Drosophila physiology, Neuroglia metabolism
- Abstract
Traumatic brain injury (TBI) is the strongest environmental risk factor for the accelerated development of neurodegenerative diseases. There are currently no therapeutics to address this due to lack of insight into mechanisms of injury progression, which are challenging to study in mammalian models. Here, we have developed and extensively characterized a head-specific approach to TBI in Drosophila , a powerful genetic system that shares many conserved genes and pathways with humans. The Drosophila TBI (dTBI) device inflicts mild, moderate, or severe brain trauma by precise compression of the head using a piezoelectric actuator. Head-injured animals display features characteristic of mammalian TBI, including severity-dependent ataxia, life span reduction, and brain degeneration. Severe dTBI is associated with cognitive decline and transient glial dysfunction, and stimulates antioxidant, proteasome, and chaperone activity. Moreover, genetic or environmental augmentation of the stress response protects from severe dTBI-induced brain degeneration and life span deficits. Together, these findings present a tunable, head-specific approach for TBI in Drosophila that recapitulates mammalian injury phenotypes and underscores the ability of the stress response to mitigate TBI-induced brain degeneration., Competing Interests: The authors declare no competing interest.
- Published
- 2020
- Full Text
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24. TDP-43, a protein central to amyotrophic lateral sclerosis, is destabilized by tankyrase-1 and -2.
- Author
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McGurk L, Rifai OM, and Bonini NM
- Subjects
- Cell Nucleus, Cytoplasm, DNA-Binding Proteins genetics, Humans, Amyotrophic Lateral Sclerosis genetics, Tankyrases genetics
- Abstract
In >95% of cases of amyotrophic lateral sclerosis (ALS) and ∼45% of frontotemporal degeneration (FTD), the RNA/DNA-binding protein TDP-43 is cleared from the nucleus and abnormally accumulates in the cytoplasm of affected brain cells. Although the cellular triggers of disease pathology remain enigmatic, mounting evidence implicates the poly(ADP-ribose) polymerases (PARPs) in TDP-43 neurotoxicity. Here we show that inhibition of the PARP enzymes tankyrase 1 and tankyrase 2 (referred to as Tnks-1/2) protect primary rodent neurons from TDP-43-associated neurotoxicity. We demonstrate that Tnks-1/2 interacts with TDP-43 via a newly defined tankyrase-binding domain. Upon investigating the functional effect, we find that interaction with Tnks-1/2 inhibits the ubiquitination and proteasomal turnover of TDP-43, leading to its stabilization. We further show that proteasomal turnover of TDP-43 occurs preferentially in the nucleus; our data indicate that Tnks-1/2 stabilizes TDP-43 by promoting cytoplasmic accumulation, which sequesters the protein from nuclear proteasome degradation. Thus, Tnks-1/2 activity modulates TDP-43 and is a potential therapeutic target in diseases associated with TDP-43, such as ALS and FTD.This article has an associated First Person interview with the first author of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2020. Published by The Company of Biologists Ltd.)
- Published
- 2020
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25. New Roles for Canonical Transcription Factors in Repeat Expansion Diseases.
- Author
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Goodman LD and Bonini NM
- Subjects
- Amyotrophic Lateral Sclerosis genetics, Frontotemporal Dementia genetics, Frontotemporal Dementia pathology, GC Rich Sequence genetics, Humans, Microsatellite Repeats genetics, Neurons metabolism, Neurons pathology, Peptides genetics, RNA biosynthesis, RNA genetics, RNA Polymerase II genetics, C9orf72 Protein genetics, DNA Repeat Expansion genetics, Transcription Factors genetics, Transcription, Genetic
- Abstract
The presence of microsatellite repeat expansions within genes is associated with >30 neurological diseases. Of interest, (GGGGCC)
>30 -repeats within C9orf72 are associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). These expansions can be 100s to 1000s of units long. Thus, it is perplexing how RNA-polymerase II (RNAPII) can successfully transcribe them. Recent investigations focusing on GGGGCC-transcription have identified specific, canonical complexes that may promote RNAPII-transcription at these GC-rich microsatellites: the DSIF complex and PAF1C. These complexes may be important for resolving the unique secondary structures formed by GGGGCC-DNA during transcription. Importantly, this process can produce potentially toxic repeat-containing RNA that can encode potentially toxic peptides, impacting neuron function and health. Understanding how transcription of these repeats occurs has implications for therapeutics in multiple diseases., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2020
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26. Repeat-associated non-AUG (RAN) translation mechanisms are running into focus for GGGGCC-repeat associated ALS/FTD.
- Author
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Goodman LD and Bonini NM
- Subjects
- Humans, Protein Biosynthesis genetics, Amyotrophic Lateral Sclerosis genetics, C9orf72 Protein genetics, Frontotemporal Dementia genetics, Repetitive Sequences, Nucleic Acid genetics
- Abstract
Many human diseases are associated with the expansion of repeat sequences within the genes. It has become clear that expressed disease transcripts bearing such long repeats can undergo translation, even in the absence of a canonical AUG start codon. Termed "RAN translation" for repeat associated non-AUG translation, this process is becoming increasingly prominent as a contributor to these disorders. Here we discuss mechanisms and variables that impact translation of the repeat sequences associated with the C9orf72 gene. Expansions of a G4C2 repeat within intron 1 of this gene are associated with the motor neuron disease ALS and dementia FTD, which comprise a clinical and pathological spectrum. RAN translation of G4C2 repeat expansions has been studied in cells in culture (ex vivo) and in the fly in vivo. Cellular states that lead to RAN translation, like stress, may be critical contributors to disease progression. Greater elucidation of the mechanisms that impact this process and the factors contributing will lead to greater understanding of the repeat expansion diseases, to the potential development of novel approaches to therapeutics, and to a greater understanding of how these players impact biological processes in the absence of disease., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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- View/download PDF
27. Poly(ADP-Ribosylation) in Age-Related Neurological Disease.
- Author
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McGurk L, Rifai OM, and Bonini NM
- Subjects
- Aging, Amyotrophic Lateral Sclerosis pathology, Animals, Brain pathology, Cells, Cultured, Drosophila, Frontotemporal Lobar Degeneration pathology, Humans, Neurodegenerative Diseases pathology, Neurons pathology, Poly Adenosine Diphosphate Ribose metabolism, Protein Aggregation, Pathological, Protein Processing, Post-Translational, ADP-Ribosylation drug effects, Amyotrophic Lateral Sclerosis genetics, Frontotemporal Lobar Degeneration genetics, Neurodegenerative Diseases genetics, Poly(ADP-ribose) Polymerase Inhibitors pharmacology
- Abstract
A central and causative feature of age-related neurodegenerative disease is the deposition of misfolded proteins in the brain. To devise novel approaches to treatment, regulatory pathways that modulate these aggregation-prone proteins must be defined. One such pathway is post-translational modification by the addition of poly(ADP-ribose) (PAR), which promotes protein recruitment and localization in several cellular contexts. Mounting evidence implicates PAR in seeding the abnormal localization and accumulation of proteins that are causative of neurodegenerative disease. Inhibitors of PAR polymerase (PARP) activity have been developed as cancer therapeutics, raising the possibility that they could be used to treat neurodegenerative disease. We focus on pathways regulated by PAR in neurodegenerative disease, with emphasis on amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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28. Toxic expanded GGGGCC repeat transcription is mediated by the PAF1 complex in C9orf72-associated FTD.
- Author
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Goodman LD, Prudencio M, Kramer NJ, Martinez-Ramirez LF, Srinivasan AR, Lan M, Parisi MJ, Zhu Y, Chew J, Cook CN, Berson A, Gitler AD, Petrucelli L, and Bonini NM
- Subjects
- Animals, Drosophila melanogaster, Humans, Mice, Transcription Factors genetics, C9orf72 Protein genetics, DNA Repeat Expansion genetics, Frontotemporal Dementia genetics, Gene Expression Regulation genetics, Nuclear Proteins genetics
- Abstract
An expanded GGGGCC hexanucleotide of more than 30 repeats (termed (G4C2)
30+ ) within C9orf72 is the most prominent mutation in familial frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) (termed C9+ ). Through an unbiased large-scale screen of (G4C2)49 -expressing Drosophila we identify the CDC73/PAF1 complex (PAF1C), a transcriptional regulator of RNA polymerase II, as a suppressor of G4C2-associated toxicity when knocked-down. Depletion of PAF1C reduces RNA and GR dipeptide production from (G4C2)30+ transgenes. Notably, in Drosophila, the PAF1C components Paf1 and Leo1 appear to be selective for the transcription of long, toxic repeat expansions, but not shorter, nontoxic expansions. In yeast, PAF1C components regulate the expression of both sense and antisense repeats. PAF1C is upregulated following (G4C2)30+ expression in flies and mice. In humans, PAF1 is also upregulated in C9+ -derived cells, and its heterodimer partner, LEO1, binds C9+ repeat chromatin. In C9+ FTD, PAF1 and LEO1 are upregulated and their expression positively correlates with the expression of repeat-containing C9orf72 transcripts. These data indicate that PAF1C activity is an important factor for transcription of the long, toxic repeat in C9+ FTD.- Published
- 2019
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29. Drosophila Ref1/ALYREF regulates transcription and toxicity associated with ALS/FTD disease etiologies.
- Author
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Berson A, Goodman LD, Sartoris AN, Otte CG, Aykit JA, Lee VM, Trojanowski JQ, and Bonini NM
- Subjects
- Animals, DNA-Binding Proteins genetics, Down-Regulation, Drosophila, Drosophila Proteins genetics, Female, Humans, Male, Motor Neurons metabolism, Nuclear Proteins genetics, RNA, Messenger genetics, Transcription Factors genetics, Up-Regulation, Amyotrophic Lateral Sclerosis genetics, Frontotemporal Dementia genetics, Gene Expression Regulation, RNA-Binding Proteins genetics
- Abstract
RNA-binding proteins (RBPs) are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the underlying disease mechanisms remain unclear. In an unbiased screen in Drosophila for RBPs that genetically interact with TDP-43, we found that downregulation of the mRNA export factor Ref1 (fly orthologue to human ALYREF) mitigated TDP-43 induced toxicity. Further, Ref1 depletion also reduced toxicity caused by expression of the C9orf72 GGGGCC repeat expansion. Ref1 knockdown lowered the mRNA levels for these related disease genes and reduced the encoded proteins with no effect on a wild-type Tau disease transgene or a control transgene. Interestingly, expression of TDP-43 or the GGGGCC repeat expansion increased endogenous Ref1 mRNA levels in the fly brain. Further, the human orthologue ALYREF was upregulated by immunohistochemistry in ALS motor neurons, with the strongest upregulation occurring in ALS cases harboring the GGGGCC expansion in C9orf72. These data support ALYREF as a contributor to ALS/FTD and highlight its downregulation as a potential therapeutic target that may affect co-existing disease etiologies.
- Published
- 2019
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- View/download PDF
30. eIF4B and eIF4H mediate GR production from expanded G4C2 in a Drosophila model for C9orf72-associated ALS.
- Author
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Goodman LD, Prudencio M, Srinivasan AR, Rifai OM, Lee VM, Petrucelli L, and Bonini NM
- Subjects
- Amyotrophic Lateral Sclerosis genetics, Animals, Animals, Genetically Modified, C9orf72 Protein genetics, DNA Repeat Expansion, Disease Models, Animal, Drosophila, Female, Gene Expression Regulation, Humans, Male, RNA metabolism, Amyotrophic Lateral Sclerosis metabolism, C9orf72 Protein metabolism, Dipeptides metabolism, Eukaryotic Initiation Factors metabolism
- Abstract
The discovery of an expanded (GGGGCC)n repeat (termed G4C2) within the first intron of C9orf72 in familial ALS/FTD has led to a number of studies showing that the aberrant expression of G4C2 RNA can produce toxic dipeptides through repeat-associated non-AUG (RAN-) translation. To reveal canonical translation factors that impact this process, an unbiased loss-of-function screen was performed in a G4C2 fly model that maintained the upstream intronic sequence of the human gene and contained a GFP tag in the GR reading frame. 11 of 48 translation factors were identified that impact production of the GR-GFP protein. Further investigations into two of these, eIF4B and eIF4H, revealed that downregulation of these factors reduced toxicity caused by the expression of expanded G4C2 and reduced production of toxic GR dipeptides from G4C2 transcripts. In patient-derived cells and in post-mortem tissue from ALS/FTD patients, eIF4H was found to be downregulated in cases harboring the G4C2 mutation compared to patients lacking the mutation and healthy individuals. Overall, these data define eIF4B and eIF4H as disease modifiers whose activity is important for RAN-translation of the GR peptide from G4C2-transcripts.
- Published
- 2019
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- View/download PDF
31. Author Correction: Aberrant activation of non-coding RNA targets of transcriptional elongation complexes contributes to TDP-43 toxicity.
- Author
-
Chung CY, Berson A, Kennerdell JR, Sartoris A, Unger T, Porta S, Kim HJ, Smith ER, Shilatifard A, Van Deerlin V, Lee VM, Chen-Plotkin A, and Bonini NM
- Abstract
The original version of this Article contained an error in the author affiliations. The affiliation of Alice Chen-Plotkin with the Department of Neurology, Perelman School of Medicine, Philadelphia, PA, 19104 USA was inadvertently omitted. This has now been corrected in both the PDF and HTML versions of the Article.
- Published
- 2019
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- View/download PDF
32. En Masse Analysis of Genetic Modifiers Informs Players and Processes in ALS.
- Author
-
Bonini NM
- Subjects
- Genetic Predisposition to Disease, Humans, Amyotrophic Lateral Sclerosis, Frontotemporal Dementia
- Published
- 2019
- Full Text
- View/download PDF
33. Poly(ADP-ribose) Engages the TDP-43 Nuclear-Localization Sequence to Regulate Granulo-Filamentous Aggregation.
- Author
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McGurk L, Gomes E, Guo L, Shorter J, and Bonini NM
- Subjects
- Amino Acid Motifs, Amino Acid Sequence, Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis metabolism, Brain metabolism, DNA-Binding Proteins chemistry, DNA-Binding Proteins genetics, Frontotemporal Lobar Degeneration genetics, Frontotemporal Lobar Degeneration metabolism, Humans, In Vitro Techniques, Kinetics, Nuclear Localization Signals genetics, Peptide Fragments chemistry, Peptide Fragments genetics, Peptide Fragments metabolism, Poly Adenosine Diphosphate Ribose pharmacology, Protein Aggregates drug effects, Protein Aggregation, Pathological genetics, Protein Aggregation, Pathological metabolism, Protein Aggregation, Pathological prevention & control, Protein Domains, DNA-Binding Proteins metabolism, Poly Adenosine Diphosphate Ribose metabolism
- Abstract
TAR DNA-binding protein of 43 kDa (TDP-43) forms granulo-filamentous aggregates in affected brain regions of >95% of patients with ALS and ∼50% of patients with frontotemporal degeneration (FTD). Furthermore, in disease, TDP-43 becomes N-terminally truncated resulting in protein deposits that are mainly composed of the C-terminal prion-like domain (PrLD). The PrLD is inherently aggregation-prone and is hypothesized to drive protein aggregation of TDP-43 in disease. Here, we establish that the N-terminal region of the protein is critical for rapid TDP-43 granulo-filamentous aggregation. We show that the biopolymer poly(ADP-ribose), or PAR, inhibits granulo-filamentous aggregation of TDP-43 by engaging PAR-binding motifs (PBMs) embedded in the TDP-43 nuclear-localization sequence. We demonstrate that progressive N-terminal truncation of TDP-43 can decelerate aggregation kinetics and promote formation of thread-like filaments. Thus, the N-terminal region and the PBMs of TDP-43 promote rapid granulo-filamentous aggregation and antagonize formation of thread-like fibrils. These findings illustrate the complexity of TDP-43 aggregation trajectories.
- Published
- 2018
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- View/download PDF
34. Aberrant activation of non-coding RNA targets of transcriptional elongation complexes contributes to TDP-43 toxicity.
- Author
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Chung CY, Berson A, Kennerdell JR, Sartoris A, Unger T, Porta S, Kim HJ, Smith ER, Shilatifard A, Van Deerlin V, Lee VM, Chen-Plotkin A, and Bonini NM
- Subjects
- Animals, Drosophila Proteins metabolism, Drosophila melanogaster metabolism, Female, Genetic Loci, HEK293 Cells, Humans, Male, Models, Biological, Nuclear Proteins metabolism, Polytene Chromosomes metabolism, Protein Binding, RNA, Small Nuclear genetics, Transcription Factors metabolism, Transcriptional Elongation Factors metabolism, DNA-Binding Proteins toxicity, RNA, Untranslated genetics, Transcription Elongation, Genetic
- Abstract
TDP-43 is the major disease protein associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-TDP). Here we identify the transcriptional elongation factor Ell-a shared component of little elongation complex (LEC) and super elongation complex (SEC)-as a strong modifier of TDP-43-mediated neurodegeneration. Our data indicate select targets of LEC and SEC become upregulated in the fly ALS/FTLD-TDP model. Among them, U12 snRNA and a stress-induced long non-coding RNA Hsrω, functionally contribute to TDP-43-mediated degeneration. We extend the findings of Hsrω, which we identify as a chromosomal target of TDP-43, to show that the human orthologue Sat III is elevated in a human cellular disease model and FTLD-TDP patient tissue. We further demonstrate an interaction between TDP-43 and human ELL2 by co-immunoprecipitation from human cells. These findings reveal important roles of Ell-complexes LEC and SEC in TDP-43-associated toxicity, providing potential therapeutic insight for TDP-43-associated neurodegeneration.
- Published
- 2018
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- View/download PDF
35. MiR-34 inhibits polycomb repressive complex 2 to modulate chaperone expression and promote healthy brain aging.
- Author
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Kennerdell JR, Liu N, and Bonini NM
- Subjects
- 3' Untranslated Regions genetics, Animals, Base Sequence, Drosophila Proteins metabolism, Gene Expression Profiling, Histones metabolism, Lysine metabolism, Methylation, MicroRNAs genetics, Models, Biological, Mutation genetics, Nerve Degeneration metabolism, Nerve Degeneration pathology, Peptides toxicity, Polycomb Repressive Complex 2 genetics, Protein Aggregates, Transcriptome genetics, Aging metabolism, Brain metabolism, Drosophila melanogaster genetics, MicroRNAs metabolism, Molecular Chaperones metabolism, Polycomb Repressive Complex 2 metabolism
- Abstract
Aging is a prominent risk factor for neurodegenerative disease. Defining gene expression mechanisms affecting healthy brain aging should lead to insight into genes that modulate susceptibility to disease. To define such mechanisms, we have pursued analysis of miR-34 mutants in Drosophila. The miR-34 mutant brain displays a gene expression profile of accelerated aging, and miR-34 upregulation is a potent suppressor of polyglutamine-induced neurodegeneration. We demonstrate that Pcl and Su(z)12, two components of polycomb repressive complex 2, (PRC2), are targets of miR-34, with implications for age-associated processes. Because PRC2 confers the repressive H3K27me3 mark, we hypothesize that miR-34 modulates PRC2 activity to relieve silencing of genes promoting healthful aging. Gene expression profiling of the brains of hypomorphic mutants in Enhancer of zeste (E(z)), the enzymatic methyltransferase component of PRC2, revealed a younger brain transcriptome profile and identified the small heat shock proteins as key genes reduced in expression with age.
- Published
- 2018
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- View/download PDF
36. Poly(ADP-Ribose) Prevents Pathological Phase Separation of TDP-43 by Promoting Liquid Demixing and Stress Granule Localization.
- Author
-
McGurk L, Gomes E, Guo L, Mojsilovic-Petrovic J, Tran V, Kalb RG, Shorter J, and Bonini NM
- Subjects
- Amyotrophic Lateral Sclerosis metabolism, Animals, COS Cells, Cell Line, Cell Nucleus metabolism, Chlorocebus aethiops, Cytoplasm metabolism, Drosophila, Female, Frontotemporal Lobar Degeneration metabolism, Male, Mammals metabolism, Neurodegenerative Diseases metabolism, Neurons metabolism, Phosphorylation physiology, Rats, Rats, Sprague-Dawley, DNA-Binding Proteins metabolism, Poly Adenosine Diphosphate Ribose metabolism
- Abstract
In amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD), cytoplasmic aggregates of hyperphosphorylated TDP-43 accumulate and colocalize with some stress granule components, but how pathological TDP-43 aggregation is nucleated remains unknown. In Drosophila, we establish that downregulation of tankyrase, a poly(ADP-ribose) (PAR) polymerase, reduces TDP-43 accumulation in the cytoplasm and potently mitigates neurodegeneration. We establish that TDP-43 non-covalently binds to PAR via PAR-binding motifs embedded within its nuclear localization sequence. PAR binding promotes liquid-liquid phase separation of TDP-43 in vitro and is required for TDP-43 accumulation in stress granules in mammalian cells and neurons. Stress granule localization initially protects TDP-43 from disease-associated phosphorylation, but upon long-term stress, stress granules resolve, leaving behind aggregates of phosphorylated TDP-43. Finally, small-molecule inhibition of Tankyrase-1/2 in mammalian cells inhibits formation of cytoplasmic TDP-43 foci without affecting stress granule assembly. Thus, Tankyrase inhibition antagonizes TDP-43-associated pathology and neurodegeneration and could have therapeutic utility for ALS and FTD., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
37. Epigenetic Regulation in Neurodegenerative Diseases.
- Author
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Berson A, Nativio R, Berger SL, and Bonini NM
- Subjects
- Aging genetics, Animals, Chromatin genetics, Humans, Models, Biological, Molecular Targeted Therapy methods, Chromatin Assembly and Disassembly physiology, Epigenesis, Genetic physiology, Histones physiology, Neurodegenerative Diseases genetics, Neurodegenerative Diseases physiopathology
- Abstract
Mechanisms of epigenetic regulation, including DNA methylation, chromatin remodeling, and histone post-translational modifications, are involved in multiple aspects of neuronal function and development. Recent discoveries have shed light on critical functions of chromatin in the aging brain, with an emerging realization that the maintenance of a healthy brain relies heavily on epigenetic mechanisms. Here, we present recent advances, with a focus on histone modifications and the implications for several neurodegenerative diseases including Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). We highlight common and unique epigenetic mechanisms among these situations and point to emerging therapeutic approaches., (Copyright © 2018. Published by Elsevier Ltd.)
- Published
- 2018
- Full Text
- View/download PDF
38. Nuclear poly(ADP-ribose) activity is a therapeutic target in amyotrophic lateral sclerosis.
- Author
-
McGurk L, Mojsilovic-Petrovic J, Van Deerlin VM, Shorter J, Kalb RG, Lee VM, Trojanowski JQ, Lee EB, and Bonini NM
- Subjects
- Adult, Aged, Amyotrophic Lateral Sclerosis genetics, Animals, Ataxin-2 genetics, Ataxin-2 metabolism, Bacterial Proteins genetics, Bacterial Proteins metabolism, Benzimidazoles pharmacology, C9orf72 Protein genetics, C9orf72 Protein metabolism, COS Cells, Cells, Cultured, Chlorocebus aethiops, Cohort Studies, DNA-Binding Proteins, Dose-Response Relationship, Drug, Female, Humans, Luminescent Proteins genetics, Luminescent Proteins metabolism, Male, Middle Aged, Motor Neurons metabolism, Mutation genetics, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Rats, Saponins pharmacology, Spinal Cord pathology, Transfection, Triterpenes pharmacology, Amyotrophic Lateral Sclerosis pathology, Cell Nucleus metabolism, Motor Neurons ultrastructure, Poly Adenosine Diphosphate Ribose metabolism
- Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating and fatal motor neuron disease. Diagnosis typically occurs in the fifth decade of life and the disease progresses rapidly leading to death within ~ 2-5 years of symptomatic onset. There is no cure, and the few available treatments offer only a modest extension in patient survival. A protein central to ALS is the nuclear RNA/DNA-binding protein, TDP-43. In > 95% of ALS patients, TDP-43 is cleared from the nucleus and forms phosphorylated protein aggregates in the cytoplasm of affected neurons and glia. We recently defined that poly(ADP-ribose) (PAR) activity regulates TDP-43-associated toxicity. PAR is a posttranslational modification that is attached to target proteins by PAR polymerases (PARPs). PARP-1 and PARP-2 are the major enzymes that are active in the nucleus. Here, we uncovered that the motor neurons of the ALS spinal cord were associated with elevated nuclear PAR, suggesting elevated PARP activity. Veliparib, a small-molecule inhibitor of nuclear PARP-1/2, mitigated the formation of cytoplasmic TDP-43 aggregates in mammalian cells. In primary spinal-cord cultures from rat, Veliparib also inhibited TDP-43-associated neuronal death. These studies uncover that PAR activity is misregulated in the ALS spinal cord, and a small-molecular inhibitor of PARP-1/2 activity may have therapeutic potential in the treatment of ALS and related disorders associated with abnormal TDP-43 homeostasis.
- Published
- 2018
- Full Text
- View/download PDF
39. Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients.
- Author
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Mordes DA, Prudencio M, Goodman LD, Klim JR, Moccia R, Limone F, Pietilainen O, Chowdhary K, Dickson DW, Rademakers R, Bonini NM, Petrucelli L, and Eggan K
- Subjects
- Animals, Brain pathology, Cohort Studies, Dipeptides, Disease Models, Animal, Drosophila, Eye pathology, Female, Frontotemporal Lobar Degeneration pathology, Glial Fibrillary Acidic Protein metabolism, Heat Shock Transcription Factors genetics, Heat Shock Transcription Factors metabolism, Humans, Male, Neurons metabolism, Signal Transduction physiology, Stem Cells metabolism, Brain metabolism, C9orf72 Protein genetics, DNA Repeat Expansion genetics, Frontotemporal Lobar Degeneration genetics, Gene Expression Regulation genetics, Heat-Shock Response physiology
- Abstract
A hexanucleotide (GGGGCC) repeat expansion in C9ORF72 is the most common genetic contributor to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Reduced expression of the C9ORF72 gene product has been proposed as a potential contributor to disease pathogenesis. Additionally, repetitive RNAs and dipeptide repeat proteins (DPRs), such as poly-GR, can be produced by this hexanucleotide expansion that disrupt a number of cellular processes, potentially contributing to neural degeneration. To better discern which of these mechanisms leads to disease-associated changes in patient brains, we analyzed gene expression data generated from the cortex and cerebellum. We found that transcripts encoding heat shock proteins (HSPs) regulated by the HSF1 transcription factor were significantly induced in C9ORF72-ALS/FTLD patients relative to both sporadic ALS/FTLD cases and controls. Treatment of human neurons with chemically synthesized DPRs was sufficient to activate a similar transcriptional response. Expression of GGGGCC repeats and also poly-GR in the brains of Drosophila lead to the upregulation of HSF1 and the same highly-conserved HSPs. Additionally, HSF1 was a modifier of poly-GR toxicity in Drosophila. Our results suggest that the expression of DPRs are associated with upregulation of HSF1 and activation of a heat shock response in C9ORF72-ALS/FTLD.
- Published
- 2018
- Full Text
- View/download PDF
40. Publisher Correction: Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease.
- Author
-
Nativio R, Donahue G, Berson A, Lan Y, Amlie-Wolf A, Tuzer F, Toledo JB, Gosai SJ, Gregory BD, Torres C, Trojanowski JQ, Wang LS, Johnson FB, Bonini NM, and Berger SL
- Abstract
In the version of this article initially published online, the fifth author's name was given as Alexander Amlie-Wolf. The correct name is Alexandre Amlie-Wolf. The error has been corrected in the print, PDF and HTML versions of this article.
- Published
- 2018
- Full Text
- View/download PDF
41. Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease.
- Author
-
Nativio R, Donahue G, Berson A, Lan Y, Amlie-Wolf A, Tuzer F, Toledo JB, Gosai SJ, Gregory BD, Torres C, Trojanowski JQ, Wang LS, Johnson FB, Bonini NM, and Berger SL
- Subjects
- Aged, Analysis of Variance, Brain metabolism, Chromatin Immunoprecipitation, Female, Genome-Wide Association Study, Histone Deacetylase 1 genetics, Humans, Male, Middle Aged, Aging, Alzheimer Disease genetics, Alzheimer Disease pathology, Alzheimer Disease physiopathology, Brain pathology, Epigenesis, Genetic physiology, Epigenomics methods, Histone Deacetylase 1 metabolism
- Abstract
Aging is the strongest risk factor for Alzheimer's disease (AD), although the underlying mechanisms remain unclear. The chromatin state, in particular through the mark H4K16ac, has been implicated in aging and thus may play a pivotal role in age-associated neurodegeneration. Here we compare the genome-wide enrichment of H4K16ac in the lateral temporal lobe of AD individuals against both younger and elderly cognitively normal controls. We found that while normal aging leads to H4K16ac enrichment, AD entails dramatic losses of H4K16ac in the proximity of genes linked to aging and AD. Our analysis highlights the presence of three classes of AD-related changes with distinctive functional roles. Furthermore, we discovered an association between the genomic locations of significant H4K16ac changes with genetic variants identified in prior AD genome-wide association studies and with expression quantitative trait loci. Our results establish the basis for an epigenetic link between aging and AD.
- Published
- 2018
- Full Text
- View/download PDF
42. TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling.
- Author
-
Berson A, Sartoris A, Nativio R, Van Deerlin V, Toledo JB, Porta S, Liu S, Chung CY, Garcia BA, Lee VM, Trojanowski JQ, Johnson FB, Berger SL, and Bonini NM
- Subjects
- Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis metabolism, Amyotrophic Lateral Sclerosis physiopathology, Animals, DNA-Binding Proteins metabolism, Disease Models, Animal, Drosophila Proteins metabolism, Drosophila melanogaster metabolism, Frontotemporal Dementia metabolism, Frontotemporal Dementia physiopathology, HEK293 Cells, Heat-Shock Proteins metabolism, Humans, Male, Middle Aged, Amyotrophic Lateral Sclerosis genetics, Chromatin Assembly and Disassembly, DNA-Binding Proteins genetics, Drosophila Proteins genetics, Drosophila melanogaster genetics, Frontotemporal Dementia genetics
- Abstract
Regulation of chromatin structure is critical for brain development and function. However, the involvement of chromatin dynamics in neurodegeneration is less well understood. Here we find, launching from Drosophila models of amyotrophic lateral sclerosis and frontotemporal dementia, that TDP-43 impairs the induction of multiple key stress genes required to protect from disease by reducing the recruitment of the chromatin remodeler Chd1 to chromatin. Chd1 depletion robustly enhances TDP-43-mediated neurodegeneration and promotes the formation of stress granules. Conversely, upregulation of Chd1 restores nucleosomal dynamics, promotes normal induction of protective stress genes, and rescues stress sensitivity of TDP-43-expressing animals. TDP-43-mediated impairments are conserved in mammalian cells, and, importantly, the human ortholog CHD2 physically interacts with TDP-43 and is strikingly reduced in level in temporal cortex of human patient tissue. These findings indicate that TDP-43-mediated neurodegeneration causes impaired chromatin dynamics that prevents appropriate expression of protective genes through compromised function of the chromatin remodeler Chd1/CHD2. Enhancing chromatin dynamics may be a treatment approach to amyotrophic lateral scleorosis (ALS)/frontotemporal dementia (FTD)., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
43. Sedimentation Velocity Analysis with Fluorescence Detection of Mutant Huntingtin Exon 1 Aggregation in Drosophila melanogaster and Caenorhabditis elegans.
- Author
-
Kim SA, D'Acunto VF, Kokona B, Hofmann J, Cunningham NR, Bistline EM, Garcia FJ, Akhtar NM, Hoffman SH, Doshi SH, Ulrich KM, Jones NM, Bonini NM, Roberts CM, Link CD, Laue TM, and Fairman R
- Subjects
- Animals, Blotting, Western, Drosophila Proteins, Electrophoresis, Gel, Two-Dimensional methods, Gene Expression Regulation, Developmental physiology, HSP70 Heat-Shock Proteins metabolism, Larva physiology, Mutation, Protein Conformation, Ultracentrifugation, Caenorhabditis elegans metabolism, Drosophila melanogaster metabolism, Huntingtin Protein chemistry
- Abstract
At least nine neurodegenerative diseases that are caused by the aggregation induced by long tracts of glutamine sequences have been identified. One such polyglutamine-containing protein is huntingtin, which is the primary factor responsible for Huntington's disease. Sedimentation velocity with fluorescence detection is applied to perform a comparative study of the aggregation of the huntingtin exon 1 protein fragment upon transgenic expression in Drosophila melanogaster and Caenorhabditis elegans. This approach allows the detection of aggregation in complex mixtures under physiologically relevant conditions. Complementary methods used to support this biophysical approach included fluorescence microscopy and semidenaturing detergent agarose gel electrophoresis, as a point of comparison with earlier studies. New analysis tools developed for the analytical ultracentrifuge have made it possible to readily identify a wide range of aggregating species, including the monomer, a set of intermediate aggregates, and insoluble inclusion bodies. Differences in aggregation in the two animal model systems are noted, possibly because of differences in levels of expression of glutamine-rich sequences. An increased level of aggregation is shown to correlate with increased toxicity for both animal models. Co-expression of the human Hsp70 in D. melanogaster showed some mitigation of aggregation and toxicity, correlating best with inclusion body formation. The comparative study emphasizes the value of the analytical ultracentrifuge equipped with fluorescence detection as a useful and rigorous tool for in situ aggregation analysis to assess commonalities in aggregation across animal model systems.
- Published
- 2017
- Full Text
- View/download PDF
44. Editorial overview: Molecular & genetic basis of disease.
- Author
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Bonini NM, Lee EB, Wasco W, and Roses AD
- Subjects
- Humans, Developmental Biology trends, Disease genetics
- Published
- 2017
- Full Text
- View/download PDF
45. ATXN2 trinucleotide repeat length correlates with risk of ALS.
- Author
-
Sproviero W, Shatunov A, Stahl D, Shoai M, van Rheenen W, Jones AR, Al-Sarraj S, Andersen PM, Bonini NM, Conforti FL, Van Damme P, Daoud H, Del Mar Amador M, Fogh I, Forzan M, Gaastra B, Gellera C, Gitler AD, Hardy J, Fratta P, La Bella V, Le Ber I, Van Langenhove T, Lattante S, Lee YC, Malaspina A, Meininger V, Millecamps S, Orrell R, Rademakers R, Robberecht W, Rouleau G, Ross OA, Salachas F, Sidle K, Smith BN, Soong BW, Sorarù G, Stevanin G, Kabashi E, Troakes C, van Broeckhoven C, Veldink JH, van den Berg LH, Shaw CE, Powell JF, and Al-Chalabi A
- Subjects
- Age of Onset, Alleles, Case-Control Studies, Female, Humans, Male, Risk, Amyotrophic Lateral Sclerosis genetics, Ataxin-2 genetics, Genetic Association Studies, Trinucleotide Repeat Expansion genetics, Trinucleotide Repeats genetics
- Abstract
We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS. We conducted a meta-analysis of the new and existing studies for the relative risks of ATXN2 intermediate repeat alleles of between 24 and 34 CAG trinucleotide repeats and ALS. There was an overall increased risk of ALS for those carrying intermediate sized trinucleotide repeat alleles (odds ratio 3.06 [95% confidence interval 2.37-3.94]; p = 6 × 10
-18 ), with an exponential relationship between repeat length and ALS risk for alleles of 29-32 repeats (R2 = 0.91, p = 0.0002). No relationship was seen for repeat length and age of onset or survival. In contrast to trinucleotide repeat diseases, intermediate ATXN2 trinucleotide repeat expansion in ALS does not predict age of onset but does predict disease risk., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2017
- Full Text
- View/download PDF
46. The Sustained Impact of Model Organisms-in Genetics and Epigenetics.
- Author
-
Bonini NM and Berger SL
- Subjects
- Animals, Caenorhabditis elegans genetics, Drosophila melanogaster genetics, Models, Animal, Molecular Biology, Saccharomyces cerevisiae genetics, Epigenomics, Genomics
- Published
- 2017
- Full Text
- View/download PDF
47. Changes in the Transcriptome of Human Astrocytes Accompanying Oxidative Stress-Induced Senescence.
- Author
-
Crowe EP, Tuzer F, Gregory BD, Donahue G, Gosai SJ, Cohen J, Leung YY, Yetkin E, Nativio R, Wang LS, Sell C, Bonini NM, Berger SL, Johnson FB, and Torres C
- Abstract
Aging is a major risk factor for many neurodegenerative disorders. A key feature of aging biology that may underlie these diseases is cellular senescence. Senescent cells accumulate in tissues with age, undergo widespread changes in gene expression, and typically demonstrate altered, pro-inflammatory profiles. Astrocyte senescence has been implicated in neurodegenerative disease, and to better understand senescence-associated changes in astrocytes, we investigated changes in their transcriptome using RNA sequencing. Senescence was induced in human fetal astrocytes by transient oxidative stress. Brain-expressed genes, including those involved in neuronal development and differentiation, were downregulated in senescent astrocytes. Remarkably, several genes indicative of astrocytic responses to injury were also downregulated, including glial fibrillary acidic protein and genes involved in the processing and presentation of antigens by major histocompatibility complex class II proteins, while pro-inflammatory genes were upregulated. Overall, our findings suggest that senescence-related changes in the function of astrocytes may impact the pathogenesis of age-related brain disorders.
- Published
- 2016
- Full Text
- View/download PDF
48. Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts.
- Author
-
Kramer NJ, Carlomagno Y, Zhang YJ, Almeida S, Cook CN, Gendron TF, Prudencio M, Van Blitterswijk M, Belzil V, Couthouis J, Paul JW 3rd, Goodman LD, Daughrity L, Chew J, Garrett A, Pregent L, Jansen-West K, Tabassian LJ, Rademakers R, Boylan K, Graff-Radford NR, Josephs KA, Parisi JE, Knopman DS, Petersen RC, Boeve BF, Deng N, Feng Y, Cheng TH, Dickson DW, Cohen SN, Bonini NM, Link CD, Gao FB, Petrucelli L, and Gitler AD
- Subjects
- Animals, C9orf72 Protein, Caenorhabditis elegans, Cells, Cultured, DNA Repeat Expansion, Dipeptides genetics, Disease Models, Animal, Drosophila melanogaster, Gene Knockdown Techniques, Humans, Nuclear Proteins genetics, Nuclear Proteins metabolism, Protein Biosynthesis, RNA, Small Interfering genetics, Repressor Proteins genetics, Saccharomyces cerevisiae Proteins genetics, Saccharomyces cerevisiae Proteins metabolism, Transcription, Genetic, Transcriptional Elongation Factors genetics, Transcriptional Elongation Factors metabolism, Amyotrophic Lateral Sclerosis genetics, Frontotemporal Dementia genetics, Gene Expression Regulation, Proteins genetics, Repressor Proteins metabolism
- Abstract
An expanded hexanucleotide repeat in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal dementia (c9FTD/ALS). Therapeutics are being developed to target RNAs containing the expanded repeat sequence (GGGGCC); however, this approach is complicated by the presence of antisense strand transcription of expanded GGCCCC repeats. We found that targeting the transcription elongation factor Spt4 selectively decreased production of both sense and antisense expanded transcripts, as well as their translated dipeptide repeat (DPR) products, and also mitigated degeneration in animal models. Knockdown of SUPT4H1, the human Spt4 ortholog, similarly decreased production of sense and antisense RNA foci, as well as DPR proteins, in patient cells. Therapeutic targeting of a single factor to eliminate c9FTD/ALS pathological features offers advantages over approaches that require targeting sense and antisense repeats separately., (Copyright © 2016, American Association for the Advancement of Science.)
- Published
- 2016
- Full Text
- View/download PDF
49. Fruit flies on the front line: the translational impact of Drosophila.
- Author
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Perrimon N, Bonini NM, and Dhillon P
- Subjects
- Animals, Cardiovascular Diseases pathology, Humans, Nerve Degeneration pathology, Drosophila melanogaster metabolism, Translational Research, Biomedical
- Abstract
Drosophila melanogaster has been adopted as one of the most-used model systems since it was first introduced by Thomas Morgan for the study of heredity in the early 20th century. Its experimental tractability and similarity of its biological pathways to those of humans have placed the model at the forefront of research into human development and disease. With the ongoing accumulation of genetic tools and assays, the fly community has at its fingertips the resources to generate diverse Drosophila disease models for the study of genes and pathways involved in a wide range of disorders. In recent years, the fly has also been used successfully for drug screening. In this Editorial, we introduce a Special Collection of reviews, interviews and original research articles that highlight some of the many ways that Drosophila has made, and continues to make, an impact on basic biological insights and translational science., (© 2016. Published by The Company of Biologists Ltd.)
- Published
- 2016
- Full Text
- View/download PDF
50. GGGGCC microsatellite RNA is neuritically localized, induces branching defects, and perturbs transport granule function.
- Author
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Burguete AS, Almeida S, Gao FB, Kalb R, Akins MR, and Bonini NM
- Subjects
- Animals, C9orf72 Protein, Cells, Cultured, Disease Models, Animal, Drosophila, Humans, RNA genetics, Amyotrophic Lateral Sclerosis pathology, Cytoplasmic Granules metabolism, Microsatellite Repeats, Neurites metabolism, Proteins genetics, RNA metabolism
- Abstract
Microsatellite expansions are the leading cause of numerous neurodegenerative disorders. Here we demonstrate that GGGGCC and CAG microsatellite repeat RNAs associated with C9orf72 in amyotrophic lateral sclerosis/frontotemporal dementia and with polyglutamine diseases, respectively, localize to neuritic granules that undergo active transport into distal neuritic segments. In cultured mammalian spinal cord neurons, the presence of neuritic GGGGCC repeat RNA correlates with neuronal branching defects, and the repeat RNA localizes to granules that label with fragile X mental retardation protein (FMRP), a transport granule component. Using a Drosophila GGGGCC expansion disease model, we characterize dendritic branching defects that are modulated by FMRP and Orb2. The human orthologs of these modifiers are misregulated in induced pluripotent stem cell-differentiated neurons (iPSNs) from GGGGCC expansion carriers. These data suggest that expanded repeat RNAs interact with the messenger RNA transport and translation machinery, causing transport granule dysfunction. This could be a novel mechanism contributing to the neuronal defects associated with C9orf72 and other microsatellite expansion diseases.
- Published
- 2015
- Full Text
- View/download PDF
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