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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
Article

Abstract

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.

Keywords

Drosophila Poly(Q) InR Neurodegeneration 

Notes

Acknowledgments

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)

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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)

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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)

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High resolution image (TIF 2104 kb)

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

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

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