دانلود مقاله ISI انگلیسی شماره 38197
عنوان فارسی مقاله

ارزیابی ترکیبات افزایش طول عمر در برابر واکنش انتقالی اتصال به DNA پروتئین 43 سمیت عصبی

کد مقاله سال انتشار مقاله انگلیسی ترجمه فارسی تعداد کلمات
38197 2013 8 صفحه PDF سفارش دهید محاسبه نشده
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عنوان انگلیسی
Evaluation of longevity enhancing compounds against transactive response DNA-binding protein-43 neuronal toxicity
منبع

Publisher : Elsevier - Science Direct (الزویر - ساینس دایرکت)

Journal : Neurobiology of Aging, Volume 34, Issue 9, September 2013, Pages 2175–2182

کلمات کلیدی
اسکلروزیس آمیوتروفیک جانبی - الگانس - نورونها - طول عمر
پیش نمایش مقاله
پیش نمایش مقاله ارزیابی ترکیبات افزایش طول عمر در برابر واکنش انتقالی اتصال به DNA پروتئین 43 سمیت عصبی

چکیده انگلیسی

Abstract In simple systems, lifespan can be extended by various methods including dietary restriction, mutations in the insulin/insulin-like growth factor (IGF) pathway or mitochondria among other processes. It is widely held that the mechanisms that extend lifespan may be adapted for diminishing age-associated pathologies. We tested whether a number of compounds reported to extend lifespan in C. elegans could reduce age-dependent toxicity caused by mutant TAR DNA-binding protein-43 in C. elegans motor neurons. Only half of the compounds tested show protective properties against neurodegeneration, suggesting that extended lifespan is not a strong predictor for neuroprotective properties. We report here that resveratrol, rolipram, reserpine, trolox, propyl gallate, and ethosuximide protect against mutant TAR DNA-binding protein-43 neuronal toxicity. Finally, of all the compounds tested, only resveratrol required daf-16 and sir-2.1 for protection, and ethosuximide showed dependence on daf-16 for its activity.

مقدمه انگلیسی

1. Introduction For more than 75 years, people have been fascinated by the discovery that rats living on a restricted diet (dietary restriction) showed increased lifespan (McCay et al., 1989), a phenomenon that is under investigation in primates (Colman et al., 2009; Mattison et al., 2012). Of great interest is the fact that not only do many organisms show increased lifespan under dietary restriction conditions but they also show decreased incidences of age-related pathologies (Anderson and Weindruch, 2012). Additional mechanisms that regulate longevity have been discovered including mitochondrial function and the insulin/insulin-like growth factor (IGF) signaling pathway. Molecular and genetic approaches have begun to decipher the cellular mechanisms of lifespan extension and this has led to the development of an industry hoping to find and develop longevity mimetics as potential therapeutic agents against age-related disease (Mercken et al., 2012). Work from model organisms like C. elegans has identified numerous compounds that extend lifespan by influencing conserved longevity mechanisms and we wondered if these compounds would be effective against age-dependent proteotoxicity. To evaluate these compounds we turned to a C. elegans model of age-dependent motor neuron toxicity ( Vaccaro et al., 2012a) and tested 11 compounds reported to extend lifespan. We identified 6 compounds that reduced mutant transactive response (TAR) DNA-binding protein-43 (TDP-43) neuronal toxicity and might be useful as candidates for testing and drug development in mammalian models of neurodegeneration.

نتیجه گیری انگلیسی

3. Results 3.1. Neuroprotection from select longevity-enhancing compounds We investigated neurodegeneration with a well-characterized transgenic C. elegans strain that expresses the full-length human TDP-43 with the A315T mutation associated with amyotrophic lateral sclerosis in the worm's GABAergic motor neurons ( Vaccaro et al., 2012a). These animals display adult-onset motility problems leading to progressive paralysis and neuronal degeneration that can be assessed over a period of 9 to 12 days ( Vaccaro et al., 2012a). With this model, we then tested 11 compounds reported to increase lifespan in C. elegans for whether they could suppress the progressive paralysis caused by mutant TDP-43 (mTDP-43). The compounds tested included: the antioxidants propyl gallate (PG), trolox (TRO), and α-lipoic acid ( Benedetti et al., 2008), the polyphenols resveratrol (RSV) ( Morselli et al., 2010) and quercetin ( Kampkotter et al., 2008), the anticonvulsant ethosuximide (ETX) ( Collins et al., 2008), reserpine (RSP) ( Srivastava et al., 2008), spermidine ( Eisenberg et al., 2009), valproic acid ( Evason et al., 2008), and thioflavin ( Alavez et al., 2011), and rolipram (ROL), a Phosphodiesterase 4 inhibitor that mimics the effects of RSV on mitochondrial function and glucose tolerance ( Park et al., 2012) (please see Supplementary Table 1 for official names and suppliers). Interestingly, only 6 compounds rescued TDP-43 toxicity: RSV, ROL, RSP, TRO, PG, and ETX ( Fig. 1, Supplementary Table 2) rescued mTDP-43 proteotoxicity at dosages previously used to increase lifespan. The 5 remaining compounds did not delay paralysis in the transgenic mTDP-43 worms ( Supplementary Fig. 1, Supplementary Table 2). We also tested whether these 6 neuroprotective compounds extended lifespan in our worms and found that all compounds except for RSV increased lifespan ( Supplementary Fig. 2, Supplementary Table 3). We also tested whether the reported effects were dependent on changes on protein expression. We found no differences in global protein expression after treatment with the 6 compounds in our transgenic worms ( Supplementary Fig. 3). Interestingly, we also observed a reduction in mTDP-43 insolubility in animals treated with TRO, PG, and ETX suggesting these compounds might aid the cellular clearance of toxic protein species ( Supplementary Fig. 3). Our data reveal an imperfect correlation between the ability of a compound to extend lifespan and reduce neuronal proteotoxicity. Lifespan-extending compounds reduce mutant TAR DNA-binding protein–43-induced ... Fig. 1. Lifespan-extending compounds reduce mutant TAR DNA-binding protein–43-induced paralysis. Compounds that reduced mutant TAR DNA-binding protein–43-induced motility defects and paralysis compared with untreated control animals included: (A) 100 μg/mL resveratrol (p < 0.001); (B) 25 μM rolipram (p < 0.001); (C) 30 μM reserpine (p < 0.05); (D) 3 mM trolox (p < 0.01); (E) 1 mM propyl gallate (p < 0.01); (F) 4 mg/mL ethosuximide (p < 0.01). See also Supplementary Table 1. Figure options 3.2. Involvement of daf-16, hsf-1, sir-2.1, and skn-1 pathways in compound-mediated neuroprotection Some of the key regulators of aging and stress signaling in C. elegans include the forkhead transcription factor daf-16, the heat shock factor transcription factor hsf-1, the sirtuin deacetylase sir-2.1 ( Kenyon, 2010), and the Nuclear respiratory factor transcription factor skn-1 ( An and Blackwell, 2003; Bishop and Guarente, 2007). To test if the 6 active compounds functioned within these pathways, we crossed our mTDP-43 transgenic animals with loss-of-function mutations or RNAi for each gene and tested if the compounds maintained neuroprotective activity. 3.2.1. Transcription factor daf-16 mediates resveratrol and ETX neuroprotection Reduced insulin/IGF pathway signaling has been implicated in aging and stress resistance (Kenyon, 2005; Kenyon et al., 1993). The downstream effector daf-16/Forkhead box O has been identified as a key target of RSV neuroprotective effects in polyglutamine toxicity ( Parker et al., 2005), and consistently, RSV was less effective at reducing mTDP-43-induced paralysis and axonal degeneration ( Fig. 2A and G). Of the remaining compounds we observed that ETX was less effective at suppressing paralysis and neurodegeneration in mTDP-43;daf-16 mutants suggesting that part of this compound's neuroprotective activity might rest within the insulin/IGF signaling pathway ( Fig. 2F and G). Transcription factor daf-16/Forkhead box O (FOXO mediates RSV and ETX ... Fig. 2. Transcription factor daf-16/Forkhead box O (FOXO mediates RSV and ETX neuroprotection. (A) RSV delayed mutant TAR DNA-binding protein-43 (mTDP-43) paralysis and this effect was dependent on daf-16. (B–E) ROL, RSP, TRO, and PG all reduced mTDP-43 paralysis compared with untreated control animals independent of daf-16. See Supplementary Table 1 for statistical information. (F) ETX delayed mTDP-43 paralysis and this was dependent on daf-16. (G) RSV and ETX failed to rescue neuronal degeneration in daf-16 mutant animals but all other compounds reduced neuronal degeneration at adult day 9 in daf-16 mutant animals compared with untreated transgenic animals. * p < 0.05; † p < 0.001; ‡ p < 0.0001. Abbreviations: ETX, ethosuximide; PG, propyl gallate; ROL, rolipram; RSP, reserpine; RSV, resveratrol; TRO, trolox. Figure options 3.2.2. Neuroprotective effects by compounds are independent of hsf-1 Chaperones are key regulators of the cellular stress response and the heat shock factor hsf-1/Heat shock factor 1 (HSF1) has been implicated in dietary restriction and proteotoxicity ( Cohen et al., 2006; Teixeira-Castro et al., 2011). We tested the different compounds in mTDP-43;hsf-1(sy441) mutants and observed no differences in the rates of paralysis or neurodegeneration compared with untreated mTDP-43 control animals ( Fig. 3 and Supplementary Table 2). Thus, although hsf-1 is important for proteotoxicity modification, it seems that neuroprotection by the 6 compounds tested here is independent of hsf-1. Neuroprotective effects by the compounds are independent of hsf-1. (A–F) All ... Fig. 3. Neuroprotective effects by the compounds are independent of hsf-1. (A–F) All compounds reduced mutant TAR DNA-binding protein-43 (mTDP-43) paralysis compared with untreated control animals independently of hsf-1. See Supplementary Table 1 for statistical information. (G) All compounds reduced neuronal degeneration in mTDP-43 animals compared with untreated control animals. * p < 0.05; † p < 0.001; ‡ p < 0.0001. Abbreviations: ETX, ethosuximide; PG, propyl gallate; ROL, rolipram; RSP, reserpine; RSV, resveratrol; TRO, trolox. Figure options 3.2.3. Resveratrol reduces neurotoxicity in a sir-2.1-dependent manner The polyphenol RSV is naturally produced by certain plant species in response to environmental stress (Signorelli and Ghidoni, 2005). Subsequent studies have shown that RSV requires sirtuins, a class of nicotinamide adenine dinucleotide-dependent deacetylases, for lifespan extension using dietary restriction (Lin et al., 2000), and was able to rescue neurodegeneration in different late age of onset disease in a Sirtuin 1-dependent manner (Kim et al., 2007; Parker et al., 2005). Thus, consistent with previous studies, RSV failed to rescue paralysis and neurodegeneration in mTDP-43;sir-2.1(ok434) mutants ( Fig. 2 and Fig. 4 and Supplementary Table 2). However, the remaining 5 compounds continued to suppress paralysis and neurodegeneration phenotypes in the absence of sir-2.1 ( Fig. 2 and Fig. 4), suggesting they function through alternative pathways. Resveratrol reduces neurotoxicity in a sir-2.1-dependent manner. (A) RSV delayed ... Fig. 4. Resveratrol reduces neurotoxicity in a sir-2.1-dependent manner. (A) RSV delayed mutant TAR DNA-binding protein-43 (mTDP-43) paralysis and this was dependent on sir-2.1. (B–F) ROL, RSP, TRO, PG, and ETX all reduced mTDP-43 paralysis compared with untreated animals independently of sir-2.1. See Supplementary Table 1 for statistical information. (G) RSV failed to rescue axonal degeneration in sir-2.1 mutant animals but all other compounds reduced neuronal degeneration in mTDP-43 animals compared with untreated control animals. * p < 0.05; ** p < 0.01; ‡ p < 0.0001. Abbreviations: ETX, ethosuximide; PG, propyl gallate; ROL, rolipram; RSP, reserpine; RSV, resveratrol; TRO, trolox. Figure options 3.2.4. Neuroprotective effects by compounds are independent of skn-1 Many genes involved in aging modulation and stress resistance overlap. We investigated whether the transcription factor skn-1, an Nuclear respiratory factor-like response factor that regulates stress resistance and longevity ( Tullet et al., 2008; Wang et al., 2010), was required for rescue of neuronal phenotypes in mTDP-43 transgenic worms after treatment with the 6 compounds. However, all the compounds continued to rescue paralysis and axonal degeneration in the absence of skn-1 ( Fig. 5 and Supplementary Table 2). Neuroprotective effects by compounds are independent of skn-1. (A–F) All ... Fig. 5. Neuroprotective effects by compounds are independent of skn-1. (A–F) All compounds reduced mutant TAR DNA-binding protein-43 (mTDP-43) paralysis compared with untreated control animals independently of skn-1. See Supplementary Table 1 for statistical information. (G) All compounds reduced neuronal degeneration in mTDP-43 animals compared with untreated control animals. ‡ p < 0.0001. Abbreviations: ETX, ethosuximide; EV, Empty Vector; PG, propyl gallate; RNAi, RNA interference; ROL, rolipram; RSP, reserpine; RSV, resveratrol; TRO, trolox.

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