Autophagy-related gene 7 is downstream of heat shock protein 27 in the regulation of eye morphology, polyglutamine toxicity, and lifespan in Drosophila
- Shih-Fen Chen†1,
- Ming-Lun Kang†1,
- Yi-Chun Chen†1,
- Hong-Wen Tang†3,
- Cheng-Wen Huang1, 4,
- Wan-Hua Li1,
- Chun-Pu Lin2,
- Chao-Yung Wang5,
- Pei-Yu Wang4Email author,
- Guang-Chao Chen3Email author and
- Horng-Dar Wang1, 2Email author
© Chen et al.; licensee BioMed Central Ltd. 2012
Received: 2 February 2012
Accepted: 23 May 2012
Published: 23 May 2012
Autophagy and molecular chaperones both regulate protein homeostasis and maintain important physiological functions. Atg7 (autophagy-related gene 7) and Hsp27 (heat shock protein 27) are involved in the regulation of neurodegeneration and aging. However, the genetic connection between Atg7 and Hsp27 is not known.
The appearances of the fly eyes from the different genetic interactions with or without polyglutamine toxicity were examined by light microscopy and scanning electronic microscopy. Immunofluorescence was used to check the effect of Atg7 and Hsp27 knockdown on the formation of autophagosomes. The lifespan of altered expression of Hsp27 or Atg7 and that of the combination of the two different gene expression were measured.
We used the Drosophila eye as a model system to examine the epistatic relationship between Hsp27 and Atg7. We found that both genes are involved in normal eye development, and that overexpression of Atg7 could eliminate the need for Hsp27 but Hsp27 could not rescue Atg7 deficient phenotypes. Using a polyglutamine toxicity assay (41Q) to model neurodegeneration, we showed that both Atg7 and Hsp27 can suppress weak, toxic effect by 41Q, and that overexpression of Atg7 improves the worsened mosaic eyes by the knockdown of Hsp27 under 41Q. We also showed that overexpression of Atg7 extends lifespan and the knockdown of Atg7 or Hsp27 by RNAi reduces lifespan. RNAi-knockdown of Atg7 expression can block the extended lifespan phenotype by Hsp27 overexpression, and overexpression of Atg7 can extend lifespan even under Hsp27 knockdown by RNAi.
We propose that Atg7 acts downstream of Hsp27 in the regulation of eye morphology, polyglutamine toxicity, and lifespan in Drosophila.
KeywordsAtg7 Hsp27 Neurodegeneration Lifespan Drosophila
The aging process results from imbalanced homeostasis combined with accumulating macromolecular damage due to different intrinsic and environmental stresses [1–3]. Protein homeostasis is important in maintaining physiological function to protect against cellular degeneration . Autophagy and molecular chaperones are two defensive systems utilized to uphold cellular protein quality and homeostasis [5, 6].
Macroautophagy (herein called autophagy) is a cellular, catabolic process that breaks down and recycles macromolecules and organelles under starvation conditions. Autophagy function is executed by a series of autophagy related genes (Atg) which are evolutionarily conserved from yeast to mammals . Autophagy participates in many physiological functions including aging and neurodegeneration [8, 9], and mounting evidence demonstrates that autophagy participates in the regulation of lifespan in different species [10–12]. In C. elegans, loss-of-function of bec-1/Atg6 or RNA interference-mediated depletion of Atg-7 or Atg-12 inhibits the extended lifespan in daf-2 mutants [13, 14], and the knockdown of bec-1 or Atg7 by RNAi abolishes dietary restriction-mediated longevity in eat-2 mutants . In addition, mutations in Atg1 Atg7 Atg18, and bec-1 reduce lifespan in C. elegans. In Drosophila, Atg7-null mutants are short-lived and hypersensitive to starvation and oxidative stress , and the neuronal overexpression of Atg8a regulates lifespan and tolerance to oxidative stress . Atg7 is an E1-like enzyme and is important for the membrane elongation of the autophagosome . Atg7 deficient mice exhibit polyubiquitinated protein accumulation and neurodegeneration  and higher levels of polyubiquitinated proteins have been detected in the aging Atg7 mutant fly head . Autophagy also protects against neurodegeneration  and the induction of autophagy by the reduction of TOR (target of rapamycin) activity reduces polyglutamine toxicity in both fly and mouse . Suppression of basal autophagy in the central nervous system causes neurodegeneration in Atg7 conditional knockout mice [19, 22].
Molecular chaperones modulate protein re-folding and facilitate the degradation of denatured proteins. Molecular chaperones are also implicated in several physiological functions: autophagy, neurodegeneration, stress tolerance, and aging [23–25]. Heat shock protein 27 (Hsp27) is a member of the ATP-independent, small heat shock protein family. Hsp27 null mutants exhibit decreased lifespan and reduced starvation tolerance , while the overexpression of Hsp27 increases lifespan and enhances stress resistance in Drosophila[27, 28]. Overexpression of Hsp27 prevents cellular polyglutamine toxicity and rescues the mosaic eyes induced by mild polyglutamine toxicity [27, 29].
Both Hsp27 and Atg7 are involved in maintaining protein quality and modulating lifespan and neurodegeneration. However, the interaction between Hsp27 and Atg7 is unknown. We report here that Atg7 is downstream of Hsp27 in the regulation of eye morphology, polyglutamine toxicity, and lifespan in Drosophila. The levels of Hsp27 and Atg7 both regulate eye morphology and the polyglutamine toxicity of 41Q. The overexpression of Atg7 rescues both the rough eye phenotype resulting from knockdown of Hsp27 as well as the more severe mosaic eye phenotype induced by the knockdown of Hsp27 under 41Q toxicity. In addition, the expression of Atg7 regulates lifespan in Drosophila and the enhanced lifespan seen with the overexpression of Hsp27 requires the expression of Atg7. Together we provide several lines of genetic evidence linking Hsp27 to Atg7 in the modulation of eye morphology, polyglutamine toxicity, and lifespan regulation.
Fly strains and maintenance
The RNAi lines were obtained from Vienna Drosophila RNAi Center (VDRC), UAS-hsp27 RNAi (#40530), UAS-hsp22 RNAi (#43632), UAS-atg1 RNAi (#16133), UAS-atg4 RNAi (#107317), UAS-atg5 RNAi (#104461), UAS-atg7 RNAi (#45560), UAS-atg8a RNAi (#43096), UAS-atg8a RNAi (#43097), UAS-atg9 RNAi (#10045), UAS-atg12 RNAi (#102362), UAS-atg18 RNAi (#105366). GMR-Gal4; UAS-41Q and GMR-Gal4/Cyo; UAS-63Q were provided by Dr. Parsa Kazemi-Esfarjani. To generate UAS-Atg7 transgenic flies, the EST clone RE27292 containing the full-length Atg7 was used to amplify the coding sequence by the primers (forward: 5’-GTACTCGAG AAGCAA AACATGAGCACGG-3’ and reverse: 5’-CATAGATCT ATCCTCGTCGCT ATCGGA-3’) and subcloned into the XhoI and BglII sites of the transgenic vector, pINDY6. The resultant construct was verified by DNA sequencing to confirm that no mutations derived from PCR amplification were made, and injected into w 1118 eggs for the generation of UAS-Atg7 transgenic flies. All flies were maintained on standard fly food as described in Liu et al. and incubated at 25°C, 65% humidity, in a 12 h/12 h light/dark-cycle fly incubator.
Fly eye image
Two-day-old flies of the different types were anaesthetized by carbon dioxide on a porous platform and the eye images were taken by light microscopy (SMZ1500, Nikon). For the scanning electron micrograph, the fly was fixed on a copper stage and the fly eye image was acquired by scanning electron microscopy (TM-1000, Hitachi). For each fly line, a total of more than 86 eye images from at least three independent crosses were examined.
RT-PCR and real-time PCR
Total RNA was prepared from about 20 flies of each specific allele and homogenized in 1 ml Trizol solution. Equal amounts (1 μg) of each DNase I-treated RNA were reverse-transcribed to cDNA with MMLV reverse transcriptase (Promega). The cDNAs were used as templates for RT-PCR or real-time PCR as described in Liu et al.. The information of the primers is available upon request.
Lifespan and starvation assays
For the lifespan assay, all the fly lines have been outcrossed with w 1118 as described previously . The newly eclosed flies of each allele were collected by sex with 30 flies per vial, maintained at 25°C, 65% humidity in a 12 h/12 h light/dark-cycle fly incubator and transferred to a new vial every 3 or 4 days until all were dead. The statistical significance was calculated by log rank test. At least three independent measurements were performed for each experiment.
For the starvation assay, newly eclosed flies of each type were collected by sex with 20 flies per vial and recovered overnight. Next day the flies were transferred to the vials with 1% agar and transferred to new agar vials daily. The numbers of the dead flies were recorded every 4 hours until all were dead. The statistical significance was calculated by student’s t test.
GFP-NLS-marked Atg7 or Hsp27 RNAi knockdown clones in the larval fat body were generated by heat shock-independent FLP/FRT induction as described previously [32, 33]. FLP/FRT method allows to examine the mitotic GFP-NLS-marked RNAi knockdown clones surrounded by the control cells that do not incorporate the RNAi knockdown in the same tissue under the same condition . Fat bodies from early third instar larva cultured in standard fly food with yeast paste (fed condition) or in dishes containing 20% sucrose only (starvation condition) for 4 hr were dissected and fixed with 4% paraformaldehyde and then examined by confocal laser scanning microscope (LSM510; Carl Zeiss Inc.) equipped with a 63x Plan-Apochromat (NA1.4) objective lens.
Autophagy-related gene 7 is downstream of heat shock protein 27 in the regulation of Drosophila eye phenotype
Knockdown of other autophagy-related genes and heat shock protein 22 does not result in a rough eye phenotype in Drosophila
Knockdown of Atg7 but not Hsp27 blocks starvation-induced autophagosome formation
Atg7 and Hsp27 attenuate the mild polyglutamine toxicity of 41Q but cannot rescue longer polyglutamine tract toxicity by 63Q
Atg7 regulates lifespan and is required for Hsp27-mediated extended lifespan in Drosophila
It has been shown that neuronal overexpression of Atg8a by appl-Gal4 extends Drosophila lifespan and increases resistance to starvation . To test whether neuronal overexpression of Atg7 enhances lifespan and starvation resistance, Atg7 was overexpressed in neurons using appl-Gal4, resulting in increases of 12% (P < 0.001) in mean lifespan and 18% (P < 0.01) in starvation resistance (Figure 5, I; Additional file 2: Table S2 and Additional file 3:Table S4). In addition, the simultaneous overexpression of Atg7 and knockdown of Hsp27 results in flies that exhibit a 21% (P < 0.001) extension in mean lifespan (Figure 5, J). Conversely, the flies possessing both knockdown of Atg7 and overexpressing Hsp27 display a reduction of 27% (P < 0.001) in mean lifespan relative to the control flies (Figure 5, J; Additional file 4 : Table S3). To further demonstrate that Atg7 functions downstream of Hsp27, we carried out the locomotion assay to measure the climbing activity of the flies with the different combination of overexpression and knockdown of Atg7 and Hsp27 along with the control flies under paraquat-induced oxidative stress. Similar to the lifespan result, the flies with simultaneous overexpression of Atg7 and knockdown of Hsp27 displayed significantly better climbing activity (42%, P ≤ 0.001) than that of the control flies (22%), and the flies with simultaneous knockdown of Atg7 and overexpression of Hsp27 exhibited a significantly lowered locomotion activity (15%, P ≤ 0.01) than that of the control flies (Additional file 5 : Figure S1). The climbing activity data in accordance with the lifespan data supports our hypothesis that Atg7 acts downstream of Hsp27. Taken together, these results indicate that as seen with Drosophila eye morphology and polyglutamine toxicity, Atg7 also acts downstream of Hsp27 in regulating lifespan.
Hsp27 and Atg7 are both implicated in the processes of aging and neurodegeneration. In this report, we provide several lines of evidence to show that Atg7 is downstream of Hsp27 in the regulation of eye morphology, polyglutamine toxicity, and lifespan. Autophagy-related genes are conserved among different species [7, 35]. Each of the identified Atgs has a role in autophagy, but their roles in other processes remains largely unclear.
In the examination of eye phenotype, we observed that the knockdown of either Hsp27 or Atg7 exhibited similar rough eye phenotypes. These effects appear to be specific to these particular molecules since the knockdown of other Atgs (Atg1 Atg4 Atg5 Atg8a Atg9 Atg12 and Atg18) or Hsp22 does not produce a similar, rough eye phenotype. The ability of Atg7 to rescue the phenotype induced by Hsp27 knockdown also suggests that a unique interaction exists between Hsp27 and Atg7. A recent study indicates that knockdown of Atg7 by GMR-Gal4 on X chromosome causes retinal degeneration . In addition, the rhabdomeres were shown degenerated in the aged atg7 d77 mutant flies . Both support our finding that RNAi knockdown of Atg7 results in rough eye in Drosophila.
Autophagy serves to protect against neurodegenerative diseases  and aberrations in autophagy have been implicated in neurodegeneration . In both fly and mouse models, induction of autophagy by inhibiting mTOR ameliorates polyglutamine toxicity . And in humans, a polymorphism study of more than 900 European Huntington’s disease patients revealed that one variant of Atg7 (Atg7 V471A ) is statistically correlated with early onset of Huntington’s disease . These findings suggest that a specific function of Atg7 is to attenuate polyglutamine toxicity and support our findings that Atg7 rescues polyglutamine toxicity by 41Q in Drosophila. Hsp27 has also been shown to reduce cellular polyglutamine toxicity  and the overexpression of Hsp27 in Drosophila rescues the pigmentation defects induced by 41Q . Several lines of evidence suggest that heat shock proteins may rely upon autophagy to reduce polyglutamine toxicity. For example, the anti-polyglutamine-aggregation activity of HspB7, one of the human small heat shock proteins, was substantially diminished in Atg5-deficient cells . In addition, it is possible that the small heat shock protein HspB8-Bag3 complex enhance Htt43Q degradation via autophagy since the treatment of the Htt43Q transfected HEK-293T and COS1 cells with an autophagy inhibitor significantly reduced HspB8-Bag3-mediated Htt43Q degradation . Furthermore, it was recently suggested that the small heat shock protein HspB7 assists in the loading of misfolded proteins or aggregates in autophagosomes . Together, these findings indicate that autophagy is downstream of small heat shock proteins and support our results that Atg7 is downstream of Hsp27.
The inhibition of autophagy results in decreased lifespan. Atg7 activity is essential for the longevity resulting from either reduced insulin signaling or caloric restriction in which depletion of Atg7 was found to block the longevity phenotypes of both daf-2 and eat-2 mutants [13, 15]. Our data showed that RNAi knockdown of Atg7 by hs-Gal4, starting from embryonic to adulthood stage, results in a shortened lifespan similar to that of the Drosophila Atg7 null mutant . Loss-of-function mutations in Atg7 as well as Atg1 Atg18, and Beclin-1 shorten lifespan in C. elegans. Several autophagy mutants including Atg7 were identified chronologically short-lived in a yeast genetic screen . However, it should be noted that not all autophagy genes are linked to aging and Atg7 is one of the conserved Atg genes that is involved in the regulation of aging in most species . Conversely, the induction of autophagy increases lifespan. The induction of autophagy by caloric restriction or reducing target of rapamycin (TOR) activity enhances lifespan  and the neuronal overexpression of Atg8a increases Drosophila lifespan . We have found that the overexpression of Atg7 extends lifespan in Drosophila and that the neuronal overexpression of Atg7 is sufficient to reverse Hsp27-knockdown-mediated, shortened lifespan. Knockdown of Atg7 blocks Hsp27-mediated extended lifespan, again supporting the model that Atg7 acts downstream of Hsp27 in the regulation of lifespan. It has been reported that in adult flies, RNAi knockdown of Atg7 by Geneswitch-Actin-Gal4 did not show reduced lifespan . This discrepancy may be due to the different Gal4 drivers used and that the knockdown of Atg7 occurring only during adulthood is insufficient to cause shortened lifespan since autophagy activity is known to be tightly regulated during development.
Yet we cannot exclude that chaperone-mediated autophagy (CMA) is involved in the connection between Hsp27 and Atg7. CMA is a specific cargo delivery process to the lumen of the lysosome, mediated by Hsc70, Hsp90, and the lysosome-associated membrane protein type 2A (LAMP-2A) [45, 46]. However, a recent study in Drosophila shows that the co-chaperone Starvin assists in the coordination of Hsc70 and HspB8 through chaperone-assisted selective autophagy, which is distinct from CMA, to depose damaged filamin for muscle maintenance . It is possible that Hsp27 may function through chaperone-assisted selective autophagy linking to Atg7.
In summary, our finding sheds new insight in the linkage of Hsp27 to Atg7 in the regulation of eye morphology, polyglutamine toxicity, and lifespan. The information provides a new aspect in the understanding how Hsp27 may connect to Atg7 to modulate certain physiological functions.
heat shock protein.
We thank Drs. Theodore Brummel, Micheline Laurent, William Ja, Pankaj Kapahi, and Chiou-Hwa Yuh for the critical reading and suggestions for the manuscript. We thank the fly lines from VDRC and Bloomington stock center, GMR-Gal4; UAS-41Q and GMR-Gal4/Cyo; UAS-63Q from Dr. Parsa Kazemi-Esfarjani. We thank the funding support from National Tsing Hua University/Chang Gung Memorial Hospital collaboration grant (101N2754E1), NTHU/McKay Hospital collaboration grant (99N2903E1), and National Science Council (100-2311-B-007-006-) to Dr. Horng-Dar Wang, National Science Council grant (100-2311-B-004-001-MY3) to Dr. Pei-Yu Wang, and Academia Sinica (AS-99-TP-B09) to Dr. Guang-Chao Chen. We are indebted for the funding support from Brain Research Center (101N2060E1) by Dr. Ann-Shyn Chiang at NTHU, the fly import assistance from Fly Core Taiwan by Dr. Chau-Ti Ting, and the transgenic fly support by Dr. Y. Henry Sun at Academia Sinica, Taipei, Taiwan.
- Haigis MC, Yankner BA: The aging stress response. Mol Cell. 2010, 40 (2): 333-344. 10.1016/j.molcel.2010.10.002.PubMed CentralView ArticlePubMedGoogle Scholar
- Koga H, Kaushik S, Cuervo AM: Protein homeostasis and aging: The importance of exquisite quality control. Ageing Res Rev. 2011, 10 (2): 205-215. 10.1016/j.arr.2010.02.001.PubMed CentralView ArticlePubMedGoogle Scholar
- Taylor RC, Dillin A: Aging as an event of proteostasis collapse. Cold Spring Harb Perspect Biol. 2011, 3 (5): a004440-10.1101/cshperspect.a004440.PubMed CentralView ArticlePubMedGoogle Scholar
- Douglas PM, Dillin A: Protein homeostasis and aging in neurodegeneration. J Cell Biol. 2010, 190 (5): 719-729. 10.1083/jcb.201005144. 2010/09/08 edPubMed CentralView ArticlePubMedGoogle Scholar
- Tyedmers J, Mogk A, Bukau B: Cellular strategies for controlling protein aggregation. Nat Rev Mol Cell Biol. 2010, 11 (11): 777-788. 10.1038/nrm2993.View ArticlePubMedGoogle Scholar
- Wong E, Cuervo AM: Integration of clearance mechanisms: the proteasome and autophagy. Cold Spring Harb Perspect Biol. 2011, 2 (12): a006734-Google Scholar
- He C, Klionsky DJ: Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009, 43: 67-93. 10.1146/annurev-genet-102808-114910.PubMed CentralView ArticlePubMedGoogle Scholar
- Kroemer G, Marino G, Levine B: Autophagy and the integrated stress response. Mol Cell. 2010, 40 (2): 280-293. 10.1016/j.molcel.2010.09.023.PubMed CentralView ArticlePubMedGoogle Scholar
- Rubinsztein DC, Marino G, Kroemer G: Autophagy and aging. Cell. 2011, 146 (5): 682-695. 10.1016/j.cell.2011.07.030.View ArticlePubMedGoogle Scholar
- Chang YY, Neufeld TP: Autophagy takes flight in Drosophila. FEBS Lett. 2010, 584 (7): 1342-1349. 10.1016/j.febslet.2010.01.006.PubMed CentralView ArticlePubMedGoogle Scholar
- Cuervo AM, Bergamini E, Brunk UT, Droge W, Ffrench M, Terman A: Autophagy and aging: the importance of maintaining "clean" cells. Autophagy. 2005, 1 (3): 131-140. 10.4161/auto.1.3.2017.View ArticlePubMedGoogle Scholar
- Madeo F, Tavernarakis N, Kroemer G: Can autophagy promote longevity?. Nat Cell Biol. 2010, 12 (9): 842-846. 10.1038/ncb0910-842.View ArticlePubMedGoogle Scholar
- Hars ES, Qi H, Ryazanov AG, Jin S, Cai L, Hu C, Liux LF: Autophagy regulates ageing in C. elegans. Autophagy. 2007, 3 (2): 93-95.View ArticlePubMedGoogle Scholar
- Melendez A, Talloczy Z, Seaman M, Eskelinen EL, Hall DH, Levine B: Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science. 2003, 301 (5638): 1387-1391. 10.1126/science.1087782.View ArticlePubMedGoogle Scholar
- Jia K, Levine B: Autophagy is required for dietary restriction-mediated life span extension in C. elegans. Autophagy. 2007, 3 (6): 597-599.View ArticlePubMedGoogle Scholar
- Toth ML, Sigmond T, Borsos E, Barna J, Erdelyi P, Takacs-Vellai K, Orosz L, Kovacs AL, Csikos G, Sass M, Vellai T: Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans. Autophagy. 2008, 4 (3): 330-338.View ArticlePubMedGoogle Scholar
- Juhasz G, Erdi B, Sass M, Neufeld TP: Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila. Genes Dev. 2007, 21 (23): 3061-3066. 10.1101/gad.1600707.PubMed CentralView ArticlePubMedGoogle Scholar
- Simonsen A, Cumming RC, Brech A, Isakson P, Schubert DR, Finley KD: Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy. 2008, 4 (2): 176-184.View ArticlePubMedGoogle Scholar
- Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K: Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006, 441 (7095): 880-884. 10.1038/nature04723.View ArticlePubMedGoogle Scholar
- Garcia-Arencibia M, Hochfeld WE, Toh PP, Rubinsztein DC: Autophagy, a guardian against neurodegeneration. Semin Cell Dev Biol. 2010, 21 (7): 691-698. 10.1016/j.semcdb.2010.02.008.PubMed CentralView ArticlePubMedGoogle Scholar
- Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ, Rubinsztein DC: Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet. 2004, 36 (6): 585-595. 10.1038/ng1362.View ArticlePubMedGoogle Scholar
- Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N: Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006, 441 (7095): 885-889. 10.1038/nature04724.View ArticlePubMedGoogle Scholar
- Lanneau D, Brunet M, Frisan E, Solary E, Fontenay M, Garrido C: Heat shock proteins: essential proteins for apoptosis regulation. J Cell Mol Med. 2008, 12 (3): 743-761. 10.1111/j.1582-4934.2008.00273.x.PubMed CentralView ArticlePubMedGoogle Scholar
- Tower J: Heat shock proteins and Drosophila aging. Exp Gerontol. 2011, 46 (5): 355-362. 10.1016/j.exger.2010.09.002.PubMed CentralView ArticlePubMedGoogle Scholar
- Voisine C, Pedersen JS, Morimoto RI: Chaperone networks: tipping the balance in protein folding diseases. Neurobiol Dis. 2010, 40 (1): 12-20. 10.1016/j.nbd.2010.05.007.PubMed CentralView ArticlePubMedGoogle Scholar
- Hao X, Zhang S, Timakov B, Zhang P: The Hsp27 gene is not required for Drosophila development but its activity is associated with starvation resistance. Cell Stress Chaperones. 2007, 12 (4): 364-372. 10.1379/CSC-308.1.PubMed CentralView ArticlePubMedGoogle Scholar
- Liao PC, Lin HY, Yuh CH, Yu LK, Wang HD: The effect of neuronal expression of heat shock proteins 26 and 27 on lifespan, neurodegeneration, and apoptosis in Drosophila. Biochem Biophys Res Commun. 2008, 376 (4): 637-641. 10.1016/j.bbrc.2008.08.161.View ArticlePubMedGoogle Scholar
- Wang HD, Kazemi-Esfarjani P, Benzer S: Multiple-stress analysis for isolation of Drosophila longevity genes. Proc Natl Acad Sci U S A. 2004, 101 (34): 12610-12615. 10.1073/pnas.0404648101.PubMed CentralView ArticlePubMedGoogle Scholar
- Wyttenbach A, Sauvageot O, Carmichael J, Diaz-Latoud C, Arrigo AP, Rubinsztein DC: Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin. Hum Mol Genet. 2002, 11 (9): 1137-1151. 10.1093/hmg/11.9.1137.View ArticlePubMedGoogle Scholar
- Liu YL, Lu WC, Brummel TJ, Yuh CH, Lin PT, Kao TY, Li FY, Liao PC, Benzer S, Wang HD: Reduced expression of alpha-1,2-mannosidase I extends lifespan in Drosophila melanogaster and Caenorhabditis elegans. Aging Cell. 2009, 8 (4): 370-379. 10.1111/j.1474-9726.2009.00471.x.PubMed CentralView ArticlePubMedGoogle Scholar
- Wang CT, Chen YC, Wang YY, Huang MH, Yen TL, Li H, Liang CJ, Sang TK, Ciou SC, Yuh CH, Wang CY, Brummel TJ, Wang HD: Reduced neuronal expression of ribose-5-phosphate isomerase enhances tolerance to oxidative stress, extends lifespan, and attenuates polyglutamine toxicity in Drosophila. Aging Cell. 2012, 11 (1): 93-103. 10.1111/j.1474-9726.2011.00762.x.PubMed CentralView ArticlePubMedGoogle Scholar
- Tang HW, Wang YB, Wang SL, Wu MH, Lin SY, Chen GC: Atg1-mediated myosin II activation regulates autophagosome formation during starvation-induced autophagy. EMBO J. 2011, 30 (4): 636-651. 10.1038/emboj.2010.338.PubMed CentralView ArticlePubMedGoogle Scholar
- Theodosiou NA, Xu T: Use of FLP/FRT system to study Drosophila development. Methods. 1998, 14 (4): 355-365. 10.1006/meth.1998.0591.View ArticlePubMedGoogle Scholar
- Morrow G, Samson M, Michaud S, Tanguay RM: Overexpression of the small mitochondrial Hsp22 extends Drosophila life span and increases resistance to oxidative stress. FASEB J. 2004, 18 (3): 598-599.PubMedGoogle Scholar
- Kourtis N, Tavernarakis N: Autophagy and cell death in model organisms. Cell Death Differ. 2009, 16 (1): 21-30. 10.1038/cdd.2008.120.View ArticlePubMedGoogle Scholar
- Midorikawa R, Yamamoto-Hino M, Awano W, Hinohara Y, Suzuki E, Ueda R, Goto S: Autophagy-dependent rhodopsin degradation prevents retinal degeneration in Drosophila. J Neurosci. 2010, 30 (32): 10703-10719. 10.1523/JNEUROSCI.2061-10.2010.View ArticlePubMedGoogle Scholar
- Wang T, Lao U, Edgar BA: TOR-mediated autophagy regulates cell death in Drosophila neurodegenerative disease. J Cell Biol. 2009, 186 (5): 703-711. 10.1083/jcb.200904090.PubMed CentralView ArticlePubMedGoogle Scholar
- Marino G, Madeo F, Kroemer G: Autophagy for tissue homeostasis and neuroprotection. Curr Opin Cell Biol. 2011, 23 (2): 198-206. 10.1016/j.ceb.2010.10.001.View ArticlePubMedGoogle Scholar
- Metzger S, Saukko M, Van Che H, Tong L, Puder Y, Riess O, Nguyen HP: Age at onset in Huntington's disease is modified by the autophagy pathway: implication of the V471A polymorphism in Atg7. Hum Genet. 2010, 128 (4): 453-459. 10.1007/s00439-010-0873-9.View ArticlePubMedGoogle Scholar
- Vos MJ, Zijlstra MP, Kanon B, van Waarde-Verhagen MA, Brunt ER, Oosterveld-Hut HM, Carra S, Sibon OC, Kampinga HH: HSPB7 is the most potent polyQ aggregation suppressor within the HSPB family of molecular chaperones. Hum Mol Genet. 2010, 19 (23): 4677-4693. 10.1093/hmg/ddq398.View ArticlePubMedGoogle Scholar
- Carra S, Seguin SJ, Lambert H, Landry J: HspB8 chaperone activity toward poly(Q)-containing proteins depends on its association with Bag3, a stimulator of macroautophagy. J Biol Chem. 2008, 283 (3): 1437-1444.View ArticlePubMedGoogle Scholar
- Vos MJ, Zijlstra MP, Carra S, Sibon OC, Kampinga HH: Small heat shock proteins, protein degradation and protein aggregation diseases. Autophagy. 2011, 7 (1): 101-103. 10.4161/auto.7.1.13935.View ArticlePubMedGoogle Scholar
- Matecic M, Smith DL, Pan X, Maqani N, Bekiranov S, Boeke JD, Smith JS: A microarray-based genetic screen for yeast chronological aging factors. PLoS Genet. 2010, 6 (4): e1000921-10.1371/journal.pgen.1000921.PubMed CentralView ArticlePubMedGoogle Scholar
- Ren C, Finkel SE, Tower J: Conditional inhibition of autophagy genes in adult Drosophila impairs immunity without compromising longevity. Exp Gerontol. 2009, 44 (3): 228-235. 10.1016/j.exger.2008.10.002.PubMed CentralView ArticlePubMedGoogle Scholar
- Arias E, Cuervo AM: Chaperone-mediated autophagy in protein quality control. Curr Opin Cell Biol. 2011, 23 (2): 184-189. 10.1016/j.ceb.2010.10.009.PubMed CentralView ArticlePubMedGoogle Scholar
- Dice JF: Chaperone-mediated autophagy. Autophagy. 2007, 3 (4): 295-299.View ArticlePubMedGoogle Scholar
- Arndt V, Dick N, Tawo R, Dreiseidler M, Wenzel D, Hesse M, Furst DO, Saftig P, Saint R, Fleischmann BK, Hoch M, Hohfeld J: Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr Biol. 2010, 20 (2): 143-148. 10.1016/j.cub.2009.11.022.View ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.