Methylene blue and dimebon inhibit aggregation of TDP‐43 in cellular models

Yamashita, Makiko; Nonaka, Takashi; Arai, Tetsuaki; Kametani, Fuyuki; Buchman, Vladimir L.; Ninkina, Natalia; Бачурин, С. О.; Akiyama, Haruhiko; Goedert, Michel; Hasegawa, Masato

doi:10.1016/j.febslet.2009.06.042

Cited by 106 publications

(75 citation statements)

References 38 publications

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“…Our experiments demonstrated that although these four compounds function within the UPR ER they operate through different branches of this pathway to achieve neuroprotection. There is growing evidence for a protective role of methylene blue against multiple forms of neurodegeneration including mTDP-43 Yamashita et al, 2009), mFUS , mutant SOD1 (Dibaj et al, 2012) mutant polyglutamine proteins (Sontag et al, 2012), and MB has shown promising effects in a Phase II clinical trial for AD (Gura, 2008). MB is not protective in adult SOD1 (Lougheed and Turnbull, 2011) or TDP-43 mice (Audet et al, 2012) and we found diminished effect on worms , and no activity in zebrafish (data not shown) after the phenotypes have been established, indicating that these compounds may not be useful for treating the disorder.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, it was demonstrated that MB can inhibit aggregate formation of a variety of proteins (Wischik et al, 1996; Taniguchi et al, 2005;Yamashita et al, 2009). To verify this hypothesis in SOD1 G93A mice, we compared the ratio of soluble versus insoluble fractions of SOD1 in the spinal cord of SOD1 G93A mice, treated or not (Fig.…”

Section: Accumulation Of Insoluble Sod1 Is Not Diminished By Mb Treatmentioning

confidence: 93%

“…-mutant TDP-43 Yamashita et al, 2009) -mutant FUS -mutant SOD1 (Dibaj et al, 2012) -mutant polyglutamine (Sontag et al, 2012) Phase II clinical trial for Alzheimer's disease (Gura, 2008) Salubrinal -Inhibits eIF2α phosphatases in the UPR ER pathway (Boyce et al, 2005). -Disrupts the PP1 complex to increase phosphorylation of eIF2α (Jousse et al, 2003) Functions inside the PERK pathway but seems not restricted to the UPR: continues to reduce mTDP-43 paralysis when PERK absent Effective in reducing mutant SOD1 toxicity in a mouse model of ALS ).…”

Section: Protein Solubilitymentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Accumulation Of Insoluble Sod1 Is Not Diminished By Mb Treatmentioning

confidence: 93%

Section: Protein Solubilitymentioning

confidence: 99%

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

Drapeau¹,

Parker²,

Kabashi³

et al. 2015

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“…[26] In rTg4510 tau-transgenic mice, MTC prevented behavioral deficits and reduced soluble brain tau levels when given before formation of NFTs in the brain, [25] but one study suggested that it could not be able to reverse established NFT pathology. [31] Other studies reported inhibitory activities of MTC on aggregation processes of prion protein, [32] α-synuclein, transactive response DNA-binding protein 43, [33,34] and huntingtin [35] …”

Section: Tais For the Treatment Of Ad: Preclinical Studies Of Methyltmentioning

confidence: 99%

Tau aggregation inhibitors: the future of Alzheimer’s pharmacotherapy?

Seripa

Solfrizzi

Imbimbo

et al. 2016

Expert Opinion on Pharmacotherapy

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“…процесс патологической агрегации белков, и все этапы этого процесса рассматриваются как потенциальные мишени для разработки новых терапевтических средств, исключительную важность приобретает описанное недавно свойство димебона влиять на формирование и/или стабильность патогенных белковых агрегатов [20,21]. Однако остается неясным, действует ли димебон непосредственно на процесс белковой агрегации или же его эффект связан с активацией процессов разрушения уже сформированных белковых фибриллярных структур, также неясно, какие именно молекулярные механизмы ответственны за антиагрегационные свойства димебона.…”

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Study into molecular targets of a neuroprotective compound dimebon using a transgenic mice line

et al. 2014

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In the present study we have used a transgenic mice overexpressing an amyloidogenic protein, gamma-synuclein, in the nervous system to address the effect of dimebon on proteinopathy progression. Neuroprotective effect of chronic dimebon administration in these mice at organismal level was confirmed by the increased lifespan. Using histological and biochemical approaches we have demonstrated that dimebon reduced the number of amyloid inclusions in spinal cord of transgenic animals and decreased the content of ubiquitinated proteins in detergent-insoluble fractions. These effects are likely to occur at the level of aggregated protein species, since transgene expression was not altered. Thus, pathological protein aggregation serves as one of dimebon targets in neurodegeneration.

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Methylene blue and dimebon inhibit aggregation of TDP‐43 in cellular models

Cited by 106 publications

References 38 publications

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

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

Tau aggregation inhibitors: the future of Alzheimer’s pharmacotherapy?

Study into molecular targets of a neuroprotective compound dimebon using a transgenic mice line

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