A High-Content Screen Identifies Novel Compounds That Inhibit Stress-Induced TDP-43 Cellular Aggregation and Associated Cytotoxicity

Boyd, Justin D.; Lee-Armandt, J. Peter; Feiler, Marisa S.; Zaarur, Nava; Liu, Min; Kraemer, Brian C.; Concannon, John; Ebata, Atsushi; Wolozin, Benjamin; Glicksman, Marcie A.

doi:10.1177/1087057113501553

Cited by 62 publications

(68 citation statements)

References 29 publications

(60 reference statements)

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“…Recently, RNA granules have been implicated in many human diseases, including neurodegeneration, cancer, autoimmune diseases and infectious diseases [2, 4, 14, 15, 17, 58, 74, 76]. RNA granules (stress granules (SGs), processing bodies (p-bodies), nuclear paraspeckles, neuronal granules etc.)…”

Section: Discussionmentioning

confidence: 99%

Pur-alpha regulates cytoplasmic stress granule dynamics and ameliorates FUS toxicity

et al. 2016

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Amyotrophic lateral Sclerosis is characterized by progressive loss of motor neurons in the brain and spinal cord. Mutations in several genes, including FUS, TDP43, Matrin 3, hnRNPA2 and other RNA binding proteins, have been linked to ALS pathology. Recently, Pur-alpha a DNA/RNA binding protein was found to bind to C9orf72 repeat expansions and could possibly play a role in the pathogenesis of ALS. When overexpressed, Pur-alpha mitigates toxicities associated with Fragile X tumor ataxia syndrome (FXTAS) and C9orf72 repeat expansion diseases in Drosophila and mammalian cell culture models. However, the function of Pur-alpha in regulating ALS pathogenesis has not been fully understood. We identified Pur-alpha as a novel component of cytoplasmic stress granules (SGs) in ALS patient cells carrying disease-causing mutations in FUS. When cells were challenged with stress, we observed that Pur-alpha co-localized with mutant FUS in ALS patient cells and became trapped in constitutive SGs. We also found that FUS physically interacted with Pur-alpha in mammalian neuronal cells. Interestingly, shRNA mediated knock down of endogenous Pur-alpha significantly reduced formation of cytoplasmic stress granules in mammalian cells suggesting that Pur-alpha is essential for the formation of SGs. Furthermore, ectopic expression of Pur-alpha blocked cytoplasmic mislocalization of mutant FUS and strongly suppressed toxicity associated with mutant FUS expression in primary motor neurons. Our data emphasizes the importance of stress granules in ALS pathogenesis and identifies Pur-alpha as a novel regulator of SG dynamics.

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Section: Discussionmentioning

confidence: 99%

Pur-alpha regulates cytoplasmic stress granule dynamics and ameliorates FUS toxicity

et al. 2016

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“…A screen to identify compounds that decrease TDP-43 aggregation was performed in cell lines and many of the molecules identified were able to suppress the impaired motility phenotype of worms expressing mutant human TDP-43 (Boyd et al, 2013). …”

Section: Using C Elegans Model For Als Drug Discoverymentioning

confidence: 99%

Worming forward: amyotrophic lateral sclerosis toxicity mechanisms and genetic interactions in Caenorhabditis elegans

Therrien

Parker

2014

Front. Genet.

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Neurodegenerative diseases share pathogenic mechanisms at the cellular level including protein misfolding, excitotoxicity and altered RNA homeostasis among others. Recent advances have shown that the genetic causes underlying these pathologies overlap, hinting at the existence of a genetic network for neurodegeneration. This is perhaps best illustrated by the recent discoveries of causative mutations for amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Once thought to be distinct entities, it is now recognized that these diseases exist along a genetic spectrum. With this wealth of discoveries comes the need to develop new genetic models of ALS and FTD to investigate not only pathogenic mechanisms linked to causative mutations, but to uncover potential genetic interactions that may point to new therapeutic targets. Given the conservation of many disease genes across evolution, Caenorhabditis elegans is an ideal system to investigate genetic interactions amongst these genes. Here we review the use of C. elegans to model ALS and investigate a putative genetic network for ALS/FTD that may extend to other neurological disorders.

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“…Boyd and colleagues have shown that drugs identified from cell based systems often have relevance in C. elegans (Boyd et al, 2013). A screen to identify compounds that decrease TDP-43 aggregation was performed in cell lines and many of the molecules identified were able to suppress the impaired motility phenotype of worms expressing mutant human TDP-43 (Boyd et al, 2013).…”

Section: Using C Elegans Model For Als Drug Discoverymentioning

confidence: 99%

Section: Using C Elegans Model For Als Drug Discoverymentioning

confidence: 99%

Chemical Genetic Screens for TDP-43 Modifiers and ALS Drug Discovery

Drapeau¹,

Parker²,

Kabashi³

et al. 2015

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information , 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE March 2015 REPORT TYPE PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBERUniversite de Montreal, L' 2900 Boul. Edouard-Montpetit Montreal H3T 1J4 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTOur objective was to screen libraries of several thousand compounds, including clinically approved drugs, for their ability to suppress the in vivo phenotypes observed in worm and fish models expressing mutant human TDP-43 related to ALS and validating hits in a mouse model. Our hypothesis was that chemical modifiers of TDP-43 in vivo function would provide new therapeutic approaches to ALS. Our screen of 3,750 FDA-approved compounds identified 20 active compounds, most of which were neuroleptics with the most potent being pimozide, as well as WithaferinA. In addition to the 4k FDA compounds, we screened 2k molecules that are structurally related to the neuroleptics as well as novel molecules. Also, we screened 4k novel derivatives of pimozide and identified several dozen active compounds. WithaferinA and pimozide were tested in TDP-43 and SOD1 mice. Results suggest that the beneficial effect of Withaferin A in mutant SOD1 mice may be due in part to an upregulation of heat shock proteins (Hsp27 and Hsp70) and to reduction in levels of misfolded SOD1 species. Motor behaviors were not significantly improved or possibly worsened by chronic treatment with pimozide. In addition, the spinal cord and brain of mice revealed and increase in TDP-43 aggregation, but no change in microgliosis, was noted. Neuromuscular transmission was improved acutely. Pimozide is being tested in an ALS clinical trial based on our neuromuscular biomarker. References……………………………………………………………………………. 18 SUBJECT TERMSAppendices INTRODUCTIONOur project was to screen libraries of small chemicals, including clinically approved drugs, for their ability to suppres...

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A High-Content Screen Identifies Novel Compounds That Inhibit Stress-Induced TDP-43 Cellular Aggregation and Associated Cytotoxicity

Cited by 62 publications

References 29 publications

Pur-alpha regulates cytoplasmic stress granule dynamics and ameliorates FUS toxicity

Pur-alpha regulates cytoplasmic stress granule dynamics and ameliorates FUS toxicity

Worming forward: amyotrophic lateral sclerosis toxicity mechanisms and genetic interactions in Caenorhabditis elegans

Chemical Genetic Screens for TDP-43 Modifiers and ALS Drug Discovery

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