Reduced prx2540-2 and elevated oxidative stress may cause stress response JNK pathway [88-92]. Western blots demonstrated that the amount of total JNK did not change but the level of phosphorylated JNK was raised (Fig. 16A and B).. In the brains of 40 days old flies, the p-JNK was higher in the heads of heterozygous dTbpsI10 mutant flies as revealed in immunohistochemical staining using DAB as substrate (Fig. 16C and D). Besides, some condensed p-JNK signals were observed around the vacuoles of the brains of heterozygous dTbpsI10 mutant flies, which was not observed in wildtype brain (Fig. 16C and D). Unlike the natural neurodegeneration, loss of dTbp activated JNK. Because JNK mediates stress responses and loss of dTbp elevated oxidative stress, our data may indicate that oxidative stress activates JNK pathway and causes apoptosis in dTbp dysfunctional condition. To confirm that the downregulation of
prx2540-2 caused by dysfunction of dTbp elevates oxidative stress
thereby activating JNK pathway, the levels of p-JNK in prx2540-2 knockdown flies were determined. Knockdown of prx2540-2 increased47
the amount of p-JNK (Fig. 16E and F). This result demonstrated that the
prx2540-2 mediates the activation of JNK pathway caused by
deactivation of dTbp. However, silencing the expression of prx2540-2, v109152, increased both p-JNK and total JNK protein levels (Fig. 16E and F). This difference between loss of dTbp and prx2540-2 with respect to the expression of JNK, can be attributed to the off-target effect of RNAi.
To confirm the downregulation of dTbp or prx2540-2 resulted in activation of JNK pathway, bskDN, a dominant negative form of
Drosophila JNK was ectopically expressed to block the activated
JNK-induced apoptosis. In Drosophila embryo, overexpression ofprx2540-2 did not affect the apoptotic cell number (Fig. 17A, B and I).
Conversely, dTbp mutant or knockdown of prx2540-2 enhanced the apoptosis phenotype (Fig. 17D, G and I). In addition, overexpression of
prx2540-2 can rescue the cell death caused by dTbp mutation as expected
(Fig. 17E and I). Furthermore, overexpression of bskDN blocked apoptosis and rescued the cell death phenotype in homozygous dTbpsI10 mutants andprx2540-2 silencing flies (Fig. 17C, F, H and I). Since blocking JNK
signaling can suppress the apoptosis caused by dysfunction of TBP or downregulation of prx2540-2, we concluded that dysfunction of dTbp or downregulation of prx2540-2 leads to oxidative stress which activates JNK signaling and apoptosis.In sum, our studies demonstrated that polyQ proteins interferes TBP activity. The deactivation of TBP downregulates the expression of
prx2540-2. Prx2540-2 downregulation further increases oxidative stress
48
and subsequently induces apoptosis through JNK activation. The above events may provide a pathomechanism of polyQ mediated
neurodegenerations.
49
Discussion
Previous studies have demonstrated that polyQ-expanded TBP forms neurotoxic aggregate that leads to SCA17 [40-46]. In this study, we first focused on the effect of polyQ expansion has on the function of TBP and its connection with SCA17, SCA3 (MJD) and HD. Next, using
microarray analysis, we found that expression of prx2540-2 is decreased profoundly when TBP is dysfunctional. Finally, we tried to associate the neurodegeneration of polyQ diseases with oxidative stress induced apoptosis.
For better understanding SCA17, we created new SCA17 Drosophila models. Compared with previous SCA17 fly models in which the
overexpression of both normal TBP and polyQ-expanded TBP induced degeneration in retina of newly eclosed flies [41], we believed that our SCA17 Drosophila model is more representative because it showed degenerative phenotypes in old age.
We proved that polyQ expansion within the NTD of TBP reduces the DNA binding ability of its CTD. In this study, TBP-109Q binds
significantly less TATA box DNA in EMSA and liquid chemiluminescent DNA pull-down assay (Fig. 2A and B). These results were also in
agreement with a previous study in which TBP-71Q exhibit considerably less DNA affinity [40]. Furthermore, we determined that polyQ expanded TBP loses DNA affinity before aggregate formation, suggesting that soluble polyQ expanded TBP monomer is dysfunctional. The results also support the idea that the soluble polyQ expanded proteins are neurotoxic.
Moreover, we showed that TBP-109Q revealed less transcription activity
50
than TBP-36Q. Accordingly, we concluded that the function of TBP
correlates its polyQ tract and that polyQ-expanded TBP is dysfunctional.
Different from other glutamine rich proteins which possesses shorter glutamine residues, TBP has a longer polyQ tract [55]. Previous studies have shown that TBP usually bears 25–42 glutamines in healthy
individuals, and more than 70% of people carry TBP with 35–38 glutamines [39, 109, 110]. Besides, the pathogenic TBP can form
heterodimers with the normal TBP [45].The relatively long polyQ tract in TBP would make normal TBP a vulnerable target to be attacked by
pathogenic TBP or other polyQ proteins, because the oligomerization of polyQ tracts is length-dependent. In this study, polyQ-expanded TBP not only exhibited more aggregate-prone trait than normal TBP, but also significantly reduced the DNA-binding and transactivation abilities of the normal TBP (Fig. 3A to C). These findings demonstrated that the
polyQ-expanded TBP interfered with the function of the normal TBP. In addition to the polyQ-expanded TBP being dysfunctional, we considered that the polyQ-expanded TBP should act in a dominant-negative manner, and that the loss of TBP function probably participates in pathology of SCA17.
Some common symptoms can be observed between polyQ diseases.
For example, SCA17 is also called Huntington’s disease-like 4 (HDL4), because pathogenic TBP can phenocopy HD [111-113]. This phenomenon can be ascribed to the fact that the same regions of neurons are impaired in these diseases. A naïve idea that common pathomechanisms among these diseases is operated could also explain the observation. In this study,
51
we showed pathogenic TBP can interact with and deactivate normal TBP (Fig. 4). Therefore, other polyQ-expanded proteins would also cause corresponding neurodegeneration through deactivation of TBP. Because the downregulation of TBP deteriorates retinal degeneration caused by the overexpression of polyQ-expanded proteins (including TBP-109Q, Atx3-78Q, Htt-97Q), the deactivation of TBP is suggested to be a common causative factor among SCA17, SCA3 and HD (Fig. 6A).
Moreover, previous studies have indicated that polyQ-expanded Htt interacts with and reduces the DNA affinity of TBP and TBP is
sequestered into protein-inclusions of polyQ-expanded Atx1, Atx2, Atx3, Atrophin-1 and Htt in vivo [25, 32, 107]. Accordingly, inactivation of TBP should be a common pathogenic factor in poly-Q mediated neurodegeneration. The link between dysfunction of TBP and
neurodegeneration is still poorly unclear. One previous study reported that the inactivation of the murine TBP leads to growth arrest and apoptosis at the embryonic blastocyst stage [30]. In this study, we demonstrated that the heterozygous dTbp mutant flies exhibits shorten lifespan and neurodegenerative phenotype (Fig. 5). Furthermore, we showed that the inactivation of dTbp increased the number of apoptotic cells in Drosophila embryos at late stages (Fig. 8). Therefore, inactivated TBP-induced apoptosis is probably conserved in flies and mammals.
Since dysfunction of TBP involves in the pathogenesis of polyQ diseases, increasing TBP activity should be beneficial. However, the results were out of our expectation because overexpression of TBP caused more severe retinal degeneration (Fig. 6 and 7). This could be due to the fact
52
that activity of TBP is closely regulated by forming nonfunctional dimer when it is overexpressed [114]. The number of insoluble inclusions was concomitantly increased when the wildtype dTbp was co-overexpressed in the flies expressing the polyQ-expanded proteins (Fig. 7). Similar to our findings, the overexpression of short polyQ peptides could accelerate aggregation and enhance cytotoxicity in Drosophila models of HD by increasing the nucleation kinetics of polyQ-expanded proteins in a
concentration-dependent and repeat-length-dependent manner [115]. This phenomenon should also clarify why overexpression of N-TBP-36Q-Myc formed inclusions in the neuroblasts of flies (Fig. 4A). Accordingly, this study strongly suggested that therapeutic intervention by replenishing or overexpressing the normal polyQ-containing proteins is imprudent in the treatment of polyQ diseases.
In the TATA box less genes, TBP is still a critical and required transcription factor [30]. In this work, we identify genes whose
expression levels were affected by TBP downregulation (Table 1). Of all the affected genes, prx2540-2 is the most likely candidate that implicates in neurodegeneration.
Furthermore, the symptoms caused by dysfunction of prx2540-2 are similar to those of dysfunction of TBP, including enhancement of
oxidative stress and apoptosis (Fig. 12, 13 and 14). Although we did not examine whether overexpression of prx2540-2 decreases the level of H2O2, there might be other signaling pathway affected by prx2540-2.
Besides, overexpression of prx2540-2 rescued the survival and mobility defects caused by TBP mutant (Fig. 14). Therefore, we argue that polyQ
53
induced neurodegeneration at less in part are caused by prx2540-2
downregulation, because TBP is deactivated by polyQ-expanded proteins.
Moreover, we suggested that the polyQ-expanded proteins induced apoptosis should be partially activated by oxidative stress induced JNK signaling (Fig. 16 and 17).
In this study we did not examine whether the antioxidants can ameliorate neurodegeneration. Nevertheless, antioxidant treatment is widely considered as therapeutic candidates for various
neurodegenerations [116-119]. Besides, inflammation has been
considered taking part in neurodegeneration [120-123]. Especially, the oxidative stress induced neuroinflammation suggests the anti-oxidation or anti-inflammation might be a practicably therapeutic strategy [60,
122-124]. Recently, a few studies have shown that peroxiredoxins are closely related to inflammation signaling [70, 125, 126]. Although the mechanism is still unclear, our works and other studies may shed a light on the development of treatment.
In summary, this study demonstrated that expanded polyQ alters the function of TBP, and polyQ-expanded TBP causes the dysfunction of normal TBP. In addition, malfunctioning TBP contributed to the
pathogenesis of SCA17 and probably participated in other polyQ diseases.
Furthermore, dysfunction of TBP enhances apoptosis and oxidative stress by reducing the expression of prx2540-2.
54
Acknowledgement
First of all, I would like to especially thank my thesis adviser, Dr.
Ming-Tsan Su, for his academic guidance and enthusiastic
encouragement throughout the research. Besides, he is very kind to
provide a great environment, let all undergraduates and graduate students in this laboratory feel supported.
And I sincerely appreciate Dr. Guey-Jen Lee-Chen and Dr. Hsiu-Mei Hsieh for teaching me and leading me in the way of research.
Then I would like to offer my special thanks to all members in C201
Drosophila laboratory for their company. I would also like to extend my
thanks to my friends in other labs for their help.I wish to acknowledge the help provided by Y.- S. Huang, S.
Artavanis-Tsakonas, L. Marsh, the Bloomington Stock Center, and the Drosophila Genomics Resource for the fly stocks, cDNA and reagents.
And I also thank the Image Core of National Taiwan Normal University and the Electron Microscope Center of National Taiwan University for confocal and SEM imaging.
Finally, I wish to thank my parents for their support and encouragement, without whom I would never have had so many opportunities.
55
References
1. Weber, J.J., et al., From Pathways to Targets: Understanding the Mechanisms behind Polyglutamine Disease. Biomed Res Int, 2014. 2014: p. 701758.
2. Mohan, R.D., S.M. Abmayr, and J.L. Workman, The expanding role for chromatin and transcription in polyglutamine disease. Curr Opin Genet Dev, 2014. 26c: p. 96-104.
3. Fiszer, A. and W.J. Krzyzosiak, Oligonucleotide-based strategies to combat polyglutamine diseases. Nucleic Acids Res, 2014. 42(11): p. 6787-810.
4. Margulis, B.A., et al., Pharmacological protein targets in polyglutamine
diseases: mutant polypeptides and their interactors. FEBS Lett, 2013. 587(13):
p. 1997-2007.
5. Ross, C.A., Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington's disease and related disorders. Neuron, 2002. 35(5): p.
819-22.
6. David, D.C., et al., Widespread protein aggregation as an inherent part of aging in C. elegans. PLoS Biol, 2010. 8(8): p. e1000450.
7. Todd, T.W. and J. Lim, Aggregation formation in the polyglutamine diseases:
protection at a cost? Mol Cells, 2013. 36(3): p. 185-94.
8. Scherzinger, E., et al., Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington's disease pathology. Proc Natl Acad Sci U S A, 1999. 96(8): p. 4604-9.
9. Steffan, J.S., et al., The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci U S A, 2000. 97(12): p. 6763-8.
10. Li, X.J., et al., A huntingtin-associated protein enriched in brain with implications for pathology. Nature, 1995. 378(6555): p. 398-402.
11. Kalchman, M.A., et al., HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain. Nat Genet, 1997.
16(1): p. 44-53.
12. Faber, P.W., et al., Huntingtin interacts with a family of WW domain proteins.
Hum Mol Genet, 1998. 7(9): p. 1463-74.
13. Gusella, J.F. and M.E. MacDonald, Huntingtin: a single bait hooks many species. Curr Opin Neurobiol, 1998. 8(3): p. 425-30.
14. Saudou, F., et al., Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell, 1998.
95(1): p. 55-66.
15. Kopito, R.R., Aggresomes, inclusion bodies and protein aggregation. Trends
56
Cell Biol, 2000. 10(12): p. 524-30.
16. Morton, A.J., et al., Progressive formation of inclusions in the striatum and hippocampus of mice transgenic for the human Huntington's disease mutation.
J Neurocytol, 2000. 29(9): p. 679-702.
17. Becher, M.W., et al., Intranuclear neuronal inclusions in Huntington's disease and dentatorubral and pallidoluysian atrophy: correlation between the density of inclusions and IT15 CAG triplet repeat length. Neurobiol Dis, 1998. 4(6): p.
387-97.
18. Taylor, J.P., et al., Aggresomes protect cells by enhancing the degradation of toxic polyglutamine-containing protein. Hum Mol Genet, 2003. 12(7): p.
749-57.
19. Lunkes, A. and J.L. Mandel, A cellular model that recapitulates major pathogenic steps of Huntington's disease. Hum Mol Genet, 1998. 7(9): p.
1355-61.
20. Lunkes, A., et al., Properties of polyglutamine expansion in vitro and in a cellular model for Huntington's disease. Philos Trans R Soc Lond B Biol Sci, 1999. 354(1386): p. 1013-9.
21. Ross, C.A. and M.A. Poirier, Protein aggregation and neurodegenerative disease. Nat Med, 2004. 10 Suppl: p. S10-7.
22. Treusch, S., D.M. Cyr, and S. Lindquist, Amyloid deposits: protection against toxic protein species? Cell Cycle, 2009. 8(11): p. 1668-74.
23. Okazawa, H., Polyglutamine diseases: a transcription disorder? Cell Mol Life Sci, 2003. 60(7): p. 1427-39.
24. Jiang, H., et al., Cell death triggered by polyglutamine-expanded huntingtin in a neuronal cell line is associated with degradation of CREB-binding protein.
Hum Mol Genet, 2003. 12(1): p. 1-12.
25. Perez, M.K., et al., Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation. J Cell Biol, 1998. 143(6): p. 1457-70.
26. Kazantsev, A., et al., Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells. Proc Natl Acad Sci U S A, 1999. 96(20): p. 11404-9.
27. Jiang, H., et al., Depletion of CBP is directly linked with cellular toxicity caused by mutant huntingtin. Neurobiol Dis, 2006. 23(3): p. 543-51.
28. Dunah, A.W., et al., Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease. Science, 2002. 296(5576): p. 2238-43.
29. van Roon-Mom, W.M., et al., TATA-binding protein in neurodegenerative disease. Neuroscience, 2005. 133(4): p. 863-72.
30. Martianov, I., S. Viville, and I. Davidson, RNA polymerase II transcription in
57
murine cells lacking the TATA binding protein. Science, 2002. 298(5595): p.
1036-9.
31. Huang, C.C., et al., Amyloid formation by mutant huntingtin: threshold, progressivity and recruitment of normal polyglutamine proteins. Somat Cell Mol Genet, 1998. 24(4): p. 217-33.
32. van Roon-Mom, W.M., et al., Insoluble TATA-binding protein accumulation in Huntington's disease cortex. Brain Res Mol Brain Res, 2002. 109(1-2): p.
1-10.
33. Yamada, M., S. Tsuji, and H. Takahashi, Pathology of CAG repeat diseases.
Neuropathology, 2000. 20(4): p. 319-25.
34. Zhang, J. and W. Gu, [Advance in research on spinocerebellar ataxia 17].
Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 2014. 31(1): p. 44-7.
35. Nakamura, K., et al., SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein. Hum Mol Genet, 2001. 10(14): p. 1441-8.
36. Fujigasaki, H., et al., CAG repeat expansion in the TATA box-binding protein gene causes autosomal dominant cerebellar ataxia. Brain, 2001. 124(Pt 10): p.
1939-47.
37. Zuhlke, C. and K. Burk, Spinocerebellar ataxia type 17 is caused by mutations in the TATA-box binding protein. Cerebellum, 2007. 6(4): p. 300-7.
38. Gerber, H.P., et al., Transcriptional activation modulated by homopolymeric glutamine and proline stretches. Science, 1994. 263(5148): p. 808-11.
39. Reid, S.J., et al., Molecular investigation of TBP allele length: a SCA17 cellular model and population study. Neurobiol Dis, 2003. 13(1): p. 37-45.
40. Friedman, M.J., et al., Polyglutamine expansion reduces the association of TATA-binding protein with DNA and induces DNA binding-independent neurotoxicity. J Biol Chem, 2008. 283(13): p. 8283-90.
41. Ren, J., et al., A Drosophila model of the neurodegenerative disease SCA17 reveals a role of RBP-J/Su(H) in modulating the pathological outcome. Hum Mol Genet, 2011. 20(17): p. 3424-36.
42. Lee, L.C., et al., Role of the CCAAT-binding protein NFY in SCA17 pathogenesis. PLoS One, 2012. 7(4): p. e35302.
43. Chen, C.M., et al., SCA17 repeat expansion: mildly expanded CAG/CAA repeat alleles in neurological disorders and the functional implications. Clin Chim Acta, 2010. 411(5-6): p. 375-80.
44. Lee, L.C., et al., Altered expression of HSPA5, HSPA8 and PARK7 in spinocerebellar ataxia type 17 identified by 2-dimensional fluorescence difference in gel electrophoresis. Clin Chim Acta, 2009. 400(1-2): p. 56-62.
58
45. Friedman, M.J., et al., Polyglutamine domain modulates the TBP-TFIIB interaction: implications for its normal function and neurodegeneration. Nat Neurosci, 2007. 10(12): p. 1519-28.
46. Huang, S., et al., Neuronal expression of TATA box-binding protein containing expanded polyglutamine in knock-in mice reduces chaperone protein response by impairing the function of nuclear factor-Y transcription factor. Brain, 2011.
134(Pt 7): p. 1943-58.
47. Yang, S., et al., Age-dependent decrease in chaperone activity impairs MANF expression, leading to Purkinje cell degeneration in inducible SCA17 mice.
Neuron, 2014. 81(2): p. 349-65.
48. Hotchkiss, R.S., et al., Cell death. N Engl J Med, 2009. 361(16): p. 1570-83.
49. Friedlander, R.M. and J. Yuan, ICE, neuronal apoptosis and neurodegeneration. Cell Death Differ, 1998. 5(10): p. 823-31.
50. Yuan, J. and B.A. Yankner, Apoptosis in the nervous system. Nature, 2000.
407(6805): p. 802-9.
51. Troy, C.M. and G.S. Salvesen, Caspases on the brain. J Neurosci Res, 2002.
69(2): p. 145-50.
52. Friedlander, R.M., Apoptosis and caspases in neurodegenerative diseases. N Engl J Med, 2003. 348(14): p. 1365-75.
53. Paulson, H.L., N.M. Bonini, and K.A. Roth, Polyglutamine disease and neuronal cell death. Proc Natl Acad Sci U S A, 2000. 97(24): p. 12957-8.
54. Gatchel, J.R. and H.Y. Zoghbi, Diseases of unstable repeat expansion:
mechanisms and common principles. Nat Rev Genet, 2005. 6(10): p. 743-55.
55. Shao, J. and M.I. Diamond, Polyglutamine diseases: emerging concepts in pathogenesis and therapy. Hum Mol Genet, 2007. 16 Spec No. 2: p. R115-23.
56. Nucifora, F.C., Jr., et al., Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science, 2001.
291(5512): p. 2423-8.
57. Bae, B.I., et al., p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease. Neuron, 2005. 47(1): p. 29-41.
58. Seto, E., et al., Wild-type p53 binds to the TATA-binding protein and represses transcription. Proc Natl Acad Sci U S A, 1992. 89(24): p. 12028-32.
59. Borza, L.R., A review on the cause-effect relationship between oxidative stress and toxic proteins in the pathogenesis of neurodegenerative diseases. Rev Med Chir Soc Med Nat Iasi, 2014. 118(1): p. 19-27.
60. Pollari, E., et al., The role of oxidative stress in degeneration of the
neuromuscular junction in amyotrophic lateral sclerosis. Front Cell Neurosci, 2014. 8: p. 131.
59
61. Federico, A., et al., Mitochondria, oxidative stress and neurodegeneration. J Neurol Sci, 2012. 322(1-2): p. 254-62.
62. Dasuri, K., L. Zhang, and J.N. Keller, Oxidative stress, neurodegeneration, and the balance of protein degradation and protein synthesis. Free Radic Biol Med, 2013. 62: p. 170-85.
63. Gandhi, S. and A.Y. Abramov, Mechanism of oxidative stress in neurodegeneration. Oxid Med Cell Longev, 2012. 2012: p. 428010.
64. Halliwell, B., Oxidative stress and neurodegeneration: where are we now? J Neurochem, 2006. 97(6): p. 1634-58.
65. Poole, L.B. and K.J. Nelson, Discovering mechanisms of signaling-mediated cysteine oxidation. Curr Opin Chem Biol, 2008. 12(1): p. 18-24.
66. Radyuk, S.N., et al., The peroxiredoxin gene family in Drosophila melanogaster. Free Radic Biol Med, 2001. 31(9): p. 1090-100.
67. Park, J., et al., 2-cys peroxiredoxins: emerging hubs determining redox
dependency of Mammalian signaling networks. Int J Cell Biol, 2014. 2014: p.
715867.
68. Rabilloud, T., et al., Proteomics analysis of cellular response to oxidative stress. Evidence for in vivo overoxidation of peroxiredoxins at their active site.
J Biol Chem, 2002. 277(22): p. 19396-401.
69. Rhee, S.G., H.Z. Chae, and K. Kim, Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell
signaling. Free Radic Biol Med, 2005. 38(12): p. 1543-52.
70. Salzano, S., et al., Linkage of inflammation and oxidative stress via release of glutathionylated peroxiredoxin-2, which acts as a danger signal. Proc Natl Acad Sci U S A, 2014. 111(33): p. 12157-62.
71. Power, J.H., et al., Peroxiredoxin 6 in human brain: molecular forms, cellular distribution and association with Alzheimer's disease pathology. Acta
Neuropathol, 2008. 115(6): p. 611-22.
72. Kim, S.H., et al., Protein levels of human peroxiredoxin subtypes in brains of patients with Alzheimer's disease and Down syndrome. J Neural Transm Suppl, 2001(61): p. 223-35.
73. Lee, Y.M., et al., Oxidative modification of peroxiredoxin is associated with drug-induced apoptotic signaling in experimental models of Parkinson disease.
J Biol Chem, 2008. 283(15): p. 9986-98.
74. Qu, D., et al., Role of Cdk5-mediated phosphorylation of Prx2 in MPTP toxicity and Parkinson's disease. Neuron, 2007. 55(1): p. 37-52.
75. De Simoni, S., J. Goemaere, and B. Knoops, Silencing of peroxiredoxin 3 and peroxiredoxin 5 reveals the role of mitochondrial peroxiredoxins in the
60
protection of human neuroblastoma SH-SY5Y cells toward MPP+. Neurosci Lett, 2008. 433(3): p. 219-24.
76. Angeles, D.C., et al., Thiol peroxidases ameliorate LRRK2 mutant-induced mitochondrial and dopaminergic neuronal degeneration in Drosophila. Hum Mol Genet, 2014. 23(12): p. 3157-65.
77. Hirth, F., Drosophila melanogaster in the study of human neurodegeneration.
CNS Neurol Disord Drug Targets, 2010. 9(4): p. 504-23.
78. Lu, B., Recent advances in using Drosophila to model neurodegenerative diseases. Apoptosis, 2009. 14(8): p. 1008-20.
79. Lu, B. and H. Vogel, Drosophila models of neurodegenerative diseases. Annu Rev Pathol, 2009. 4: p. 315-42.
80. Cauchi, R.J. and M. van den Heuvel, The fly as a model for neurodegenerative diseases: is it worth the jump? Neurodegener Dis, 2006. 3(6): p. 338-56.
81. Ambegaokar, S.S., B. Roy, and G.R. Jackson, Neurodegenerative models in Drosophila: polyglutamine disorders, Parkinson disease, and amyotrophic lateral sclerosis. Neurobiol Dis, 2010. 40(1): p. 29-39.
82. Casci, I. and U.B. Pandey, A fruitful endeavor: Modeling ALS in the fruit fly.
82. Casci, I. and U.B. Pandey, A fruitful endeavor: Modeling ALS in the fruit fly.