Molecular Neurobiology

, Volume 56, Issue 2, pp 1310–1329 | Cite as

Tissue-Specific Upregulation of Drosophila Insulin Receptor (InR) Mitigates Poly(Q)-Mediated Neurotoxicity by Restoration of Cellular Transcription Machinery

  • Kritika Raj
  • Surajit SarkarEmail author


Polyglutamine [poly(Q)] disorders are a class of trinucleotide repeat expansion neurodegenerative disorders which are dominantly inherited and progressively acquired with age. This group of disorders entail the characteristic formation of protein aggregates leading to widespread loss of neurons in different regions of the brain. SCA3 and HD, the two most commonly occurring types of poly(Q) disorders were examined in the present study. With the aim of elucidating novel genetic modifiers of poly(Q) disorders, the Drosophila insulin receptor (InR) was identified as a potential suppressor of poly(Q)-induced neurotoxicity and degeneration. We demonstrate for the first time that targeted upregulation of InR could effectively mitigate poly(Q)-mediated neurodegeneration in fly models. A significant reduction in poly(Q)-mediated cellular stress and apoptosis was noted upon InR overexpression in poly(Q) background. We further reveal that targeted upregulation of InR causes a substantial reduction in poly(Q) aggregate formation with the residual inclusion bodies localised to the cytoplasm. We also demonstrate that InR achieves suppression of poly(Q) toxicity by replenishing the cellular pool of CREB binding protein and improving the histone acetylation status of the cell. This leads to restoration of the cellular transcriptional machinery which is otherwise severely compromised in poly(Q) disease conditions. Interestingly, there also appeared a possibility of autophagy-mediated rescue of poly(Q) phenotype due to upregulation of InR. Therefore, our study strongly suggests that modulation of the insulin signalling pathway could be an effective therapeutic intervention against poly(Q) disorders.


Drosophila Poly(Q) InR Neurodegeneration 



We are thankful to J. Troy Littleton (Massachusetts Institute of Technology, USA), Hugo Stocker (Institute for Molecular Systems Biology, Switzerland), Ernst Hafen (Institute for Molecular Systems Biology, Switzerland), Justin P. Kumar (Indiana University, Bloomington, USA) and T. Lilja (Stockholm University, USA) for providing different fly stocks and some antibodies used in this study. We also thank Bloomington Stock Center, USA, for providing some fly stocks. We also thank DST-FIST(L2) support to the department. We are grateful to Ms. Nabanita Sarkar for technical support.

Funding Information

This work was supported by research grants (No. BT/PR15492/MED/122/46/2016) from the Department of Biotechnology (DBT), Government of India, New Delhi, India, to S.S. KR is supported by the Senior Research Fellowship (Ref. No. Schs/SRF/AA/139/F-227/2013-14) from the University Grant Commission (UGC), New Delhi, India.

Supplementary material

12035_2018_1160_Fig10_ESM.png (2.4 mb)
Fig. S1

InR protects against poly(Q) induced neurotoxicity throughout the lifespan of the fly. (a-l) Bright field pictures of external surface of the adult eye. (a-c) In comparison to control, GMR-GAL4 driven expression of SCA3trQ78(S) resulted in degenerated adult eye which was substantially rescued upon coexpression of InR, 1-day post eclosion, (d-f) In comparison to control, UAS-SCA3trQ78(S)-GMR-GAL4/CyO flies exhibited aggravated loss of pigmentation and roughening of eye surface 5 days post eclosion which was inhibited upon coexpression of InR, (g-i) 10 days post eclosion, SCA3 expressing flies showed appearance of necrotic patches on the eye surface which was suppressed in InR co-expressing flies, (j-l) In comparison to exaggerated neurotoxicity and large necrotic patches in poly(Q) expressing flies, InR co-expressing flies sustained rescue of disease phenotypes to a significant extent even 20 days post eclosion (PNG 2461 kb)

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High resolution image (TIF 4189 kb)
12035_2018_1160_Fig11_ESM.png (827 kb)
Fig. S2

Rescue potential of InR against SCA3 induced neurodegeneration is better than DIAP1 and depends on its intrinsic growth promoting properties. (a-d) Bright field pictures of external surface of the adult eye. (a) Coexpression of GFP with SCA3trQ78(S) did not affect disease phenotype, (b) Coexpression of DIAP1 partially rescued SCA3 disease phenotypes but showed reduced rescue capacity as compared to InR, (c) GMR-GAL4 driven expression of InR increased eye size, (d) RNAi mediated downregulation of InR did not produce any perceivable phenotype (PNG 826 kb)

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High resolution image (TIF 1294 kb)
12035_2018_1160_Fig12_ESM.png (652 kb)
Fig. S3

Tissue specific upregulation of InR does not alter the expression level of a neutral transgene. (a-d) Fluorescence images of larval eye discs analysed for GFP expression. (a) GMR-GAL4 driven expression of UAS-GFP transgene in the eye region, (b-d) unaltered expression level of UAS-GFP transgene following its coexpression with SCA3trQ78(S), InR or both of them together, (e) Histogram representation of relative GFP fluorescence intensities in various genotypes. (Scale bars: a-d = 50 μm) (PNG 651 kb)

12035_2018_1160_MOESM3_ESM.tif (6.8 mb)
High resolution image (TIF 7003 kb)
12035_2018_1160_Fig13_ESM.png (1.3 mb)
Fig. S4

InR-CFP allele is also capable of mitigating poly(Q) induced neurotoxicity in early and late stages of development. (a-c) Fluorescence images of larval eye discs examined for CFP expression. (a-b) Absence of CFP expression in control and SCA3 expressing eye discs, (c) Bright CFP expression in the eye region following coexpression of InR-CFP in disease background. (d-f) Bright field pictures of external surface of the adult eye. (d) w;GMR-GAL4/+;+/+ control, (e) Degenerated adult eye following expression of SCA3trQ78(S), (f) Rescue of disease phenotypes and improved eye morphology upon coexpression of InR-CFP. (g-i) Fluorescence images of adult heads examined for CFP expression. (g-h) Absence of CFP expression in control and SCA3 expressing heads, (i) Bright CFP expressing puncta in the eye region of the head following coexpression of InR-CFP in disease background (PNG 1352 kb)

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High resolution image (TIF 2076 kb)
12035_2018_1160_Fig14_ESM.png (910 kb)
Fig. S5

Overexpression of InR reduces AO and TUNEL positive cells in larval eye disc and adult eye sections respectively. (a-c, d-f) Fluorescence images of larval eye discs and adult eye sections subjected to AO staining and TUNEL assay respectively. (a, d) Absence of apoptotic cell death in control tissues, (b, e) Robust upregulation of AO and TUNEL positive signals following expression of SCA3trQ78(S), (d, f) Reduced AO and TUNEL staining, thereby lessened apoptotic cell death upon coexpression of InR. (Scale bars: a-c = 50 μm; d-f = 20 μm) (PNG 909 kb)

12035_2018_1160_MOESM5_ESM.tif (959 kb)
High resolution image (TIF 958 kb)
12035_2018_1160_Fig15_ESM.png (1.3 mb)
Fig. S6

Targeted downregulation of dCBP in the eye causes degeneration which aggravates upon poly(Q) expression. (a-f) Bright field pictures of external surface of the adult eye. (a) w;GMR-GAL4/+;+/+ control, (b, c) Downregulation of dCBP using dCBPΔBHQ or dCBP-RNAi leads to abnormal development of eye, (d) Degenerated adult eye following expression of SCA3trQ78(S), (e, f) Expression of dCBPΔBHQ or dCBP-RNAi in SCA3trQ78(S) background exacerbates the poly(Q) toxicity (PNG 1366 kb)

12035_2018_1160_MOESM6_ESM.tif (2.1 mb)
High resolution image (TIF 2104 kb)


  1. 1.
    Landles C, Bates GP (2004) Huntingtin and the molecular pathogenesis of Huntington's disease. Fourth in molecular medicine review series. EMBO Rep 5(10):958–963. PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Everett CM, Wood NW (2004) Trinucleotide repeats and neurodegenerative disease. Brain 127(Pt 11):2385–2405. PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Pearson CE, Nichol Edamura K, Cleary JD (2005) Repeat instability: mechanisms of dynamic mutations. Nat Rev Genet 6(10):729–742. PubMedCrossRefGoogle Scholar
  4. 4.
    Thompson LM (2008) Neurodegeneration: a question of balance. Nature 452(7188):707–708. PubMedCrossRefGoogle Scholar
  5. 5.
    Ordway JM, Tallaksen-Greene S, Gutekunst CA, Bernstein EM, Cearley JA, Wiener HW, Dure LS, Lindsey R et al (1997) Ectopically expressed CAG repeats cause intranuclear inclusions and a progressive late onset neurological phenotype in the mouse. Cell 91(6):753–763PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Wellington CL, Ellerby LM, Hackam AS, Margolis RL, Trifiro MA, Singaraja R, McCutcheon K, Salvesen GS et al (1998) Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J Biol Chem 273(15):9158–9167CrossRefGoogle Scholar
  7. 7.
    Fan HC, Ho LI, Chi CS, Chen SJ, Peng GS, Chan TM, Lin SZ, Harn HJ (2014) Polyglutamine (PolyQ) diseases: genetics to treatments. Cell Transplant 23(4–5):441–458. PubMedCrossRefGoogle Scholar
  8. 8.
    Chen S, Berthelier V, Yang W, Wetzel R (2001) Polyglutamine aggregation behavior in vitro supports a recruitment mechanism of cytotoxicity. J Mol Biol 311(1):173–182. PubMedCrossRefGoogle Scholar
  9. 9.
    Michalik A, Van Broeckhoven C (2003) Pathogenesis of polyglutamine disorders: aggregation revisited. Hum Mol Genet 12(2):R173–R186. PubMedCrossRefGoogle Scholar
  10. 10.
    Taylor JP, Taye AA, Campbell C, Kazemi-Esfarjani P, Fischbeck KH, Min KT (2003) Aberrant histone acetylation, altered transcription, and retinal degeneration in a Drosophila model of polyglutamine disease are rescued by CREB-binding protein. Genes Dev 17(12):1463–1468. PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Saudou F, Finkbeiner S, Devys D, Greenberg ME (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95(1):55–66PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF et al (2004) Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet 36(6):585–595. CrossRefPubMedGoogle Scholar
  13. 13.
    Annenkov A (2009) The insulin-like growth factor (IGF) receptor type 1 (IGF1R) as an essential component of the signalling network regulating neurogenesis. Mol Neurobiol 40(3):195–215. PubMedCrossRefGoogle Scholar
  14. 14.
    Johnson-Farley NN, Travkina T, Cowen DS (2006) Cumulative activation of akt and consequent inhibition of glycogen synthase kinase-3 by brain-derived neurotrophic factor and insulin-like growth factor-1 in cultured hippocampal neurons. J Pharmacol Exp Ther 316(3):1062–1069. PubMedCrossRefGoogle Scholar
  15. 15.
    Schechter R, Yanovitch T, Abboud M, Johnson G 3rd, Gaskins J (1998) Effects of brain endogenous insulin on neurofilament and MAPK in fetal rat neuron cell cultures. Brain Res 808(2):270–278PubMedCrossRefGoogle Scholar
  16. 16.
    Moroo I, Yamada T, Makino H, Tooyama I, McGeer PL, McGeer EG, Hirayama K (1994) Loss of insulin receptor immunoreactivity from the substantia nigra pars compacta neurons in Parkinson's disease. Acta Neuropathol 87(4):343–348PubMedCrossRefGoogle Scholar
  17. 17.
    Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands JR et al (2005) Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease—is this type 3 diabetes? J Alzheimers Dis 7(1):63–80PubMedCrossRefGoogle Scholar
  18. 18.
    Parisi F, Riccardo S, Daniel M, Saqcena M, Kundu N, Pession A, Grifoni D, Stocker H et al (2011) Drosophila insulin and target of rapamycin (TOR) pathways regulate GSK3 beta activity to control Myc stability and determine Myc expression in vivo. BMC Biol 9:65. PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Singh MD, Raj K, Sarkar S (2014) Drosophila Myc, a novel modifier suppresses the poly(Q) toxicity by modulating the level of CREB binding protein and histone acetylation. Neurobiol Dis 63:48–61. PubMedCrossRefGoogle Scholar
  20. 20.
    Bonini NM (1999) A genetic model for human polyglutamine-repeat disease in Drosophila melanogaster. Philos Trans R Soc Lond Ser B Biol Sci 354(1386):1057–1060. CrossRefGoogle Scholar
  21. 21.
    Warrick JM, Chan HY, Gray-Board GL, Chai Y, Paulson HL, Bonini NM (1999) Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet 23(4):425–428. PubMedCrossRefGoogle Scholar
  22. 22.
    Hay BA, Wolff T, Rubin GM (1994) Expression of baculovirus P35 prevents cell death in Drosophila. Development 120(8):2121–2129PubMedPubMedCentralGoogle Scholar
  23. 23.
    Lin DM, Goodman CS (1994) Ectopic and increased expression of Fasciclin II alters motoneuron growth cone guidance. Neuron 13(3):507–523PubMedCrossRefGoogle Scholar
  24. 24.
    Yang MY, Armstrong JD, Vilinsky I, Strausfeld NJ, Kaiser K (1995) Subdivision of the Drosophila mushroom bodies by enhancer-trap expression patterns. Neuron 15(1):45–54PubMedCrossRefGoogle Scholar
  25. 25.
    Almudi I, Poernbacher I, Hafen E, Stocker H (2013) The Lnk/SH2B adaptor provides a fail-safe mechanism to establish the insulin receptor-Chico interaction. Cell Commun Signal 11(1):26. PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Weiss KR, Kimura Y, Lee WC, Littleton JT (2012) Huntingtin aggregation kinetics and their pathological role in a Drosophila Huntington's disease model. Genetics 190(2):581–600. PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Steinert JR, Campesan S, Richards P, Kyriacou CP, Forsythe ID, Giorgini F (2012) Rab11 rescues synaptic dysfunction and behavioural deficits in a Drosophila model of Huntington's disease. Hum Mol Genet 21(13):2912–2922. PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Kumar JP, Jamal T, Doetsch A, Turner FR, Duffy JB (2004) CREB binding protein functions during successive stages of eye development in Drosophila. Genetics 168(2):877–893. PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Chanu SI, Sarkar S (2016) Targeted downregulation of dMyc suppresses pathogenesis of human neuronal Tauopathies in Drosophila by limiting heterochromatin relaxation and tau hyperphosphorylation. Mol Neurobiol 54(4):2706–2719. PubMedCrossRefGoogle Scholar
  30. 30.
    Lilja T, Qi D, Stabell M, Mannervik M (2003) The CBP coactivator functions both upstream and downstream of Dpp/screw signaling in the early Drosophila embryo. Dev Biol 262(2):294–302PubMedCrossRefGoogle Scholar
  31. 31.
    Brand AH, Perrimon N (1993) Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118(2):401–415PubMedGoogle Scholar
  32. 32.
    Chan HY, Warrick JM, Andriola I, Merry D, Bonini NM (2002) Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila. Hum Mol Genet 11(23):2895–2904PubMedCrossRefGoogle Scholar
  33. 33.
    Hay BA, Wassarman DA, Rubin GM (1995) Drosophila homologs of baculovirus inhibitor of apoptosis proteins function to block cell death. Cell 83(7):1253–1262CrossRefGoogle Scholar
  34. 34.
    Branco J, Al-Ramahi I, Ukani L, Perez AM, Fernandez-Funez P, Rincon-Limas D, Botas J (2008) Comparative analysis of genetic modifiers in Drosophila points to common and distinct mechanisms of pathogenesis among polyglutamine diseases. Hum Mol Genet 17(3):376–390. PubMedCrossRefGoogle Scholar
  35. 35.
    Guo L, Giasson BI, Glavis-Bloom A, Brewer MD, Shorter J, Gitler AD, Yang X (2014) A cellular system that degrades misfolded proteins and protects against neurodegeneration. Mol Cell 55(1):15–30. PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Quinn WG, Harris WA, Benzer S (1974) Conditioned behavior in Drosophila melanogaster. Proc Natl Acad Sci U S A 71(3):708–712PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Cohen-Carmon D, Meshorer E (2012) Polyglutamine (polyQ) disorders: the chromatin connection. Nucleus 3(5):433–441. PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Fahrbach SE (2006) Structure of the mushroom bodies of the insect brain. Annu Rev Entomol 51:209–232. PubMedCrossRefGoogle Scholar
  39. 39.
    Kurusu M, Awasaki T, Masuda-Nakagawa LM, Kawauchi H, Ito K, Furukubo-Tokunaga K (2002) Embryonic and larval development of the Drosophila mushroom bodies: concentric layer subdivisions and the role of fasciclin II. Development 129(2):409–419PubMedGoogle Scholar
  40. 40.
    Chou AH, Yeh TH, Kuo YL, Kao YC, Jou MJ, Hsu CY, Tsai SR, Kakizuka A et al (2006) Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-xL. Neurobiol Dis 21(2):333–345. PubMedCrossRefGoogle Scholar
  41. 41.
    Meier P, Silke J, Leevers SJ, Evan GI (2000) The Drosophila caspase DRONC is regulated by DIAP1. EMBO J 19(4):598–611. PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L et al (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6(7):797–801. PubMedCrossRefGoogle Scholar
  43. 43.
    Kasten FH (1967) Cytochemical studies with acridine orange and the influence of dye contaminants in the staining of nucleic acids. Int Rev Cytol 21:141–202PubMedCrossRefGoogle Scholar
  44. 44.
    Fan Y, Bergmann A (2010) The cleaved-Caspase-3 antibody is a marker of Caspase-9-like DRONC activity in Drosophila. Cell Death Differ 17(3):534–539. PubMedCrossRefGoogle Scholar
  45. 45.
    Chai Y, Koppenhafer SL, Bonini NM, Paulson HL (1999) Analysis of the role of heat shock protein (Hsp) molecular chaperones in polyglutamine disease. J Neurosci 19(23):10338–10347PubMedCrossRefGoogle Scholar
  46. 46.
    Velazquez JM, Sonoda S, Bugaisky G, Lindquist S (1983) Is the major Drosophila heat shock protein present in cells that have not been heat shocked? J Cell Biol 96(1):286–290PubMedCrossRefGoogle Scholar
  47. 47.
    Strzyz P (2017) Mechanisms of diseases: Excessive polyQ tracts curb autophagy. Nat Rev Mol Cell Biol 18(6):344. PubMedCrossRefGoogle Scholar
  48. 48.
    Wong E, Cuervo AM (2010) Autophagy gone awry in neurodegenerative diseases. Nat Neurosci 13(7):805–811. PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Krench M, Littleton JT (2017) Neurotoxicity pathways in Drosophila models of the polyglutamine disorders. Curr Top Dev Biol 121:201–223. PubMedCrossRefGoogle Scholar
  50. 50.
    Labbadia J, Morimoto RI (2015) The biology of proteostasis in aging and disease. Annu Rev Biochem 84:435–464. PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Kroemer G, Marino G, Levine B (2010) Autophagy and the integrated stress response. Mol Cell 40(2):280–293. PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K et al (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441(7095):885–889. PubMedCrossRefGoogle Scholar
  53. 53.
    Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M et al (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441(7095):880–884. PubMedCrossRefGoogle Scholar
  54. 54.
    Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ (2007) Potential therapeutic applications of autophagy. Nat Rev Drug Discov 6(4):304–312. PubMedCrossRefGoogle Scholar
  55. 55.
    Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451(7182):1069–1075. PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Yamamoto A, Cremona ML, Rothman JE (2006) Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J Cell Biol 172(5):719–731. PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    DeVorkin L, Gorski SM (2014) LysoTracker staining to aid in monitoring autophagy in Drosophila. Cold Spring Harb Protoc 2014(9):951–958. PubMedCrossRefGoogle Scholar
  58. 58.
    Wu J, Dang Y, Su W, Liu C, Ma H, Shan Y, Pei Y, Wan B et al (2006) Molecular cloning and characterization of rat LC3A and LC3B—two novel markers of autophagosome. Biochem Biophys Res Commun 339(1):437–442. PubMedCrossRefGoogle Scholar
  59. 59.
    Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y et al (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19(21):5720–5728. PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Tanida I, Ueno T, Kominami E (2008) LC3 and autophagy. Methods Mol Biol 445:77–88. PubMedCrossRefGoogle Scholar
  61. 61.
    Schmidt T, Landwehrmeyer GB, Schmitt I, Trottier Y, Auburger G, Laccone F, Klockgether T, Volpel M et al (1998) An isoform of ataxin-3 accumulates in the nucleus of neuronal cells in affected brain regions of SCA3 patients. Brain Pathol 8(4):669–679PubMedCrossRefGoogle Scholar
  62. 62.
    Paulson HL, Perez MK, Trottier Y, Trojanowski JQ, Subramony SH, Das SS, Vig P, Mandel JL et al (1997) Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3. Neuron 19(2):333–344PubMedCrossRefGoogle Scholar
  63. 63.
    Ye L, Maji S, Sanghera N, Gopalasingam P, Gorbunov E, Tarasov S, Epstein O, Klein-Seetharaman J (2017) Structure and dynamics of the insulin receptor: implications for receptor activation and drug discovery. Drug Discov Today 22:1092–1102. PubMedCrossRefGoogle Scholar
  64. 64.
    Hamelers IH, Steenbergh PH (2003) Interactions between estrogen and insulin-like growth factor signaling pathways in human breast tumor cells. Endocr Relat Cancer 10(2):331–345PubMedCrossRefGoogle Scholar
  65. 65.
    Mester J, Redeuilh G (2008) Proliferation of breast cancer cells: regulation, mediators, targets for therapy. Anti Cancer Agents Med Chem 8(8):872–885CrossRefGoogle Scholar
  66. 66.
    Coelho CM, Leevers SJ (2000) Do growth and cell division rates determine cell size in multicellular organisms? J Cell Sci 113(Pt 17):2927–2934PubMedGoogle Scholar
  67. 67.
    Edgar BA (2006) How flies get their size: genetics meets physiology. Nat Rev Genet 7(12):907–916. PubMedCrossRefGoogle Scholar
  68. 68.
    Konishi T, Takeyasu A, Natsume T, Furusawa Y, Hieda K (2011) Visualization of heavy ion tracks by labeling 3'-OH termini of induced DNA strand breaks. J Radiat Res 52(4):433–440PubMedCrossRefGoogle Scholar
  69. 69.
    Escudero LM, Freeman M (2007) Mechanism of G1 arrest in the Drosophila eye imaginal disc. BMC Dev Biol 7(13):13. PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Yamaguchi M, Hirose F, Inoue YH, Shiraki M, Hayashi Y, Nishi Y, Matsukage A (1999) Ectopic expression of human p53 inhibits entry into S phase and induces apoptosis in the Drosophila eye imaginal disc. Oncogene 18(48):6767–6775. PubMedCrossRefGoogle Scholar
  71. 71.
    McCampbell A, Taylor JP, Taye AA, Robitschek J, Li M, Walcott J, Merry D, Chai Y et al (2000) CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet 9(14):2197–2202PubMedCrossRefGoogle Scholar
  72. 72.
    Nucifora FC Jr, Sasaki M, Peters MF, Huang H, Cooper JK, Yamada M, Takahashi H, Tsuji S et al (2001) Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science 291(5512):2423–2428. PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Ludlam WH, Taylor MH, Tanner KG, Denu JM, Goodman RH, Smolik SM (2002) The acetyltransferase activity of CBP is required for wingless activation and H4 acetylation in Drosophila melanogaster. Mol Cell Biol 22(11):3832–3841PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Puig O, Tjian R (2005) Transcriptional feedback control of insulin receptor by dFOXO/FOXO1. Genes Dev 19(20):2435–2446. PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Sakamoto K, Iwasaki K, Sugiyama H, Tsuji Y (2009) Role of the tumor suppressor PTEN in antioxidant responsive element-mediated transcription and associated histone modifications. Mol Biol Cell 20(6):1606–1617. PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Chen YL, Law PY, Loh HH (2008) NGF/PI3K signaling-mediated epigenetic regulation of delta opioid receptor gene expression. Biochem Biophys Res Commun 368(3):755–760. PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Wyss-Coray T (2016) Ageing, neurodegeneration and brain rejuvenation. Nature 539(7628):180–186. PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Fernandez R, Tabarini D, Azpiazu N, Frasch M, Schlessinger J (1995) The Drosophila insulin receptor homolog: a gene essential for embryonic development encodes two receptor isoforms with different signaling potential. EMBO J 14(14):3373–3384PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    White MF, Kahn CR (1994) The insulin signaling system. J Biol Chem 269(1):1–4PubMedGoogle Scholar
  80. 80.
    Li CR, Guo D, Pick L (2013) Independent signaling by Drosophila insulin receptor for axon guidance and growth. Front Physiol 4:385. PubMedCrossRefGoogle Scholar
  81. 81.
    Reis SD, Pinho BR, Oliveira JM (2016) Modulation of molecular chaperones in Huntington's disease and other polyglutamine disorders. Mol Neurobiol 54:5829–5854. PubMedCrossRefGoogle Scholar
  82. 82.
    Kaur J, Debnath J (2015) Autophagy at the crossroads of catabolism and anabolism. Nat Rev Mol Cell Biol 16(8):461–472. PubMedCrossRefGoogle Scholar
  83. 83.
    Hyttinen JM, Amadio M, Viiri J, Pascale A, Salminen A, Kaarniranta K (2014) Clearance of misfolded and aggregated proteins by aggrephagy and implications for aggregation diseases. Ageing Res Rev 18:16–28. PubMedCrossRefGoogle Scholar
  84. 84.
    Lamark T, Johansen T (2012) Aggrephagy: selective disposal of protein aggregates by macroautophagy. Int J Cell Biol 2012:736905. PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Yang H, Hu HY (2016) Sequestration of cellular interacting partners by protein aggregates: implication in a loss-of-function pathology. FEBS J 283(20):3705–3717. PubMedCrossRefGoogle Scholar
  86. 86.
    Ogryzko VV, Schiltz RL, Russanova V, Howard BH, Nakatani Y (1996) The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 87(5):953–959CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of GeneticsUniversity of Delhi South CampusNew DelhiIndia

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