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(Ramirez et al., 2006), PARK11/GIGYF2 (Lautier et al., 2008), and PARK13/HTRA2 (Strauss et al., 2005). The functional analyses of these PD-associated proteins suggest multiple defective pathways that may lead to DA neurodegeneration (Dawson and Dawson, 2003; Thomas and Beal, 2007) (Fig. 1.1). PD pathogenesis: SNCA/α-syn The first PD gene discovered was SNCA/α-syn (Polymeropoulos et al., 1997), which encodes natively unfolded 140 amino-acid protein with unknown function. α-Syn has been detected in presynaptic nerve termini (Jakes et al., 1994), and shown to bind to lipids (Perrin et al., 2000). Originally identified as a non-amyloid-β component of AD amyloid (Ueda et al., 1993), α-syn, similar to amyloid-β and polyglutamine-repeat containing proteins, is prone to aggregation. Subsequent analysis of SNCA gene has revealed that multiplication of SNCA loci enhanced α-syn expression, resulting in the protein aggregation and the onset of PD (Singleton et al., 2003). Since the formation of Lewy bodies is a central pathological feature of both familial and sporadic forms of PD, most current PD research focuses on α-syn aggregation and cellular mechanisms involved in ameliorating it. For example, accumulation of α-syn has been shown to impair UPS function (Stefanis et al., 2001; Zhang et al., 2008; Nonaka et al., 2009), and α-syn is degraded by lysosomes (Webb et al., 2003; Cuervo et al., 2004). Furthermore, overexpression of α-syn blocks 4
endoplasmic reticulum (ER) to Golgi trafficking (Cooper et al., 2006; Gitler et al., 2008), and expression of mutant α-syn induces ER stress (Smith et al., 2005). Additionally, α- syn may also be targeted to mitochondria and impair complex I function via cryptic mitochondrial targeting signal (Devi et al., 2008). As discussed below, functional analysis of six out of nine PD-associated gene products illustrate involvement of defective proteasomal and lysosomal protein degradation machineries, as well as inadequate cellular response to mitochondrial and oxidative stress in PD pathogenesis. PD pathogenesis: proteasomal protein degradation The most common protein degradation machinery of the cell is the UPS, which consists of a variety of proteins including the ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), ubiquitin ligases (E3), ubiquitin carboxyl-terminal hydrolases (UCHL), and proteasomal subunits. Briefly, E1, E2, and E3 are involved in the processes of activating, transferring, and binding ubiquitins (Ubs) to target proteins that are degraded by proteasomes. After proteolysis, Ubs that are attached to the degraded products are recycled by UCHL to maintain the cytoplasmic Ub pool. Misfolded proteins, such as α-syn (Stefanis et al., 2001; Zhang et al., 2008; Nonaka et al., 2009), polyglutamine-repeat containing gene products (Bence et al., 2001; Bennett et al., 2007; Iwata et al., 2009), and amyloid-β (Almeida et al., 2006) have been shown to impair UPS function. 5
Page 1 and 2: IDENTIFICATION OF NEUROPROTECTIVE G
Page 3 and 4: ABSTRACT Recent functional analyses
Page 5 and 6: E3 Ubiquitin ligase ER Endoplasmic
Page 7 and 8: RT-PCR Reverse transcriptase polyme
Page 9 and 10: TAG-278 Temporary assigned gene 278
Page 11 and 12: p38 Mitogen-activated protein kinas
Page 13 and 14: ACKNOWLEDGMENTS First and foremost,
Page 15 and 16: CONTENTS ABSTRACT .................
Page 17 and 18: a. Abstract .......................
Page 19 and 20: LIST OF FIGURES 1.1. Schematic repr
Page 21 and 22: Parkinson disease CHAPTER ONE INTRO
Page 23: al., 2006) and torsinA (Cao et al.,
Page 27 and 28: c-Jun N-terminal kinase and caspase
Page 29 and 30: lysosomal protease promotes α-syn
Page 31 and 32: ROS, which may oxidize DA (a neurot
Page 33 and 34: together, although anti-oxidant act
Page 35 and 36: multicellular eukaryotic model orga
Page 37 and 38: C. elegans PD models C. elegans off
Page 39 and 40: Current studies To investigate gene
Page 41 and 42: Specific outcomes and future direct
Page 43 and 44: Corti, O., Hampe, C., Koutnikova, H
Page 45 and 46: Lautier, C., Goldwurm, S., Dürr, A
Page 47 and 48: Scherzer, C.R., Jensen, R.V., Gulla
Page 49 and 50: Willcox, B.J., Donlon, T.A., He, Q.
Page 51 and 52: Table 1.2. Summary of selected inve
Page 53 and 54: FIGURE LEGENDS Fig. 1.1. Schematic
Page 55 and 56: ABSTRACT Genomic multiplication of
Page 57 and 58: et al., 2003). Maintenance of DA ne
Page 59 and 60: Pdat-1::FLAG-R05D11.6, Punc-54::DsR
Page 61 and 62: Biochemicals) and 1:10000 horseradi
Page 63 and 64: was washed with 100 µl RNase-free
Page 65 and 66: and effectively discerned via RNAi
Page 67 and 68: protein. The primary RNAi screen of
Page 69 and 70: expressing a polyglutamine::GFP fus
Page 71 and 72: stage (Fig. 2.2B-D). Two genes exhi
Page 73 and 74: with strong expression localized to
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Our data demonstrating that the C.
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disparate datasets, such as those o
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Driscoll, M., Gerstbrein, B. (2003)
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Singleton, A.B., Farrer, M., Johnso
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Table 2.2. Bioinformatic associatio
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Table 2.4. Results of all genes kno
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C09G12.9 Tumor susceptibility gene
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C32B5.13 Cathepsin H precursor C32B
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D1014.3 Alpha-soluble NSF attachmen
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F22B7.5 DNAJA3, mitochondrial precu
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F40F4.5 Tubulin alpha-ubiquitous ch
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F54F7.5 Serine/threonine kinase 24
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K07A9.2 CAMK1 K07C11.9 Hypothetical
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R74.4 DNAJB1 precursor T01B7.4 Pept
Page 103 and 104:
T22D1.9 PSMD2 T22F3.2 Ubiquitin spe
Page 105 and 106:
Y38F2AL.3 Vacuolar ATP synthase sub
Page 107 and 108:
Y73C8C.8 CENPE variant protein (Fra
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Table 2.5. Summary of RNAi knockdow
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Figure 2.2 91
Page 113 and 114:
Figure 2.4 93
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Figure 2.6 95
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FIGURE LEGENDS Figure 2.1. RNAi kno
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came from genes that were co-expres
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ABSTRACT Multiple Parkinson disease
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vacuoles (mammalian equivalent of l
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neuroprotection when the animals we
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To investigate the genetic interact
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illustrated that α-syn overexpress
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main contributor of α-syn phosphor
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Hoozemans, J.J., van Haastert, E.S.
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Figure 3.2 115
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FIGURE LEGENDS Figure 3.1. RAB3A, R
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CHAPTER FOUR RNA INTERFERENCE SCREE
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INTRODUCTION Central to Parkinson d
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thermotolerance (Lithgow et al., 19
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mCherry were transferred onto NGM p
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20°C for 72 hrs. The gravid adults
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pathways downstream of DAF-2 exclud
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were assayed by growing the RNAi-tr
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while DOG treatment enhanced α-syn
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enhance α-syn misfolding in a daf-
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REFERENCES Bar-On, P., Crews, L., K
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Lesage, S., Brice, A. (2009) Hum Mo
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Table 4.1. Summary of genes analyze
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C12D12.2 Excitatory amino acid tran
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C47B2.2 n/a C47C12.6 Amiloride-sens
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F18A1.5 Replication protein A F18E3
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F46E10.10 Malate dehydrogenase F46E
Page 171 and 172:
K08H10.1 Dentin sialophosphoprotein
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T05A10.5 Cysteine-rich secretory pr
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W03G9.6 Platelet-activating factor
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Y58G8A.1 Acetylcholine receptor sub
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Table 4.2. Summary of positive gene
Page 181 and 182:
Figure 4.1 161
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Figure 4.3 163
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Figure 4.5 165
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Figure 4.7 167
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Figure 4.4. Graph illustrating the
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in yeast but not in humans. In yeas
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kinase that has also been shown to
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mir-2/mir-43/mir-250/mir-797 superf
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of djr-1.1 and djr-1.2 enhance α-s
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expensive, since they require high
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Ambros, V. (2001) Cell 107, 823-826
Page 203 and 204:
Yi, J., Tang, X.M. (1999) Cell Res
Page 205 and 206:
Figure 5.2 185
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