Mechanisms of aluminium neurotoxicity in oxidative stress-induced ...

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INTRODUCTION Mitochondrial dysfunction 36 Many data support now a role for aberrant mitochondrial form and function in the pathogenesis of PD (Schapira 2008). Mitochondria are essential for the generation of cellular energy through oxidative phosphorylation. They are also the major cellular source of free radicals and are implicated in the regulation and initiation of cell death pathways and in calcium homeostasis. Mitochondria dysfunction can lead to insufficient ATP production hence impairing all ATP-dependent cellular processes and generate and accumulate ROS, rendering then cells more vulnerable to oxidative stress and other interconnected processes, including excitotoxicity. Originally, MPTP toxicity and reduction of complex I activity in the SNpc of PD patients provided evidence for the participation of mitochondrial pathways in PD (Schapira et al. 1992, Mann et al. 1994). Moreover, demonstration of the involvement of PD-associated genes products in mitochondrial function reinforced the connection between PD and mitochondrial biology (Dodson and Guo 2007). Mutations of these PD-associated genes will likely disrupt mitochondrial function and affect the cellular response to oxidative stress. PINK1, a mitochondrial serine-threonine kinase that shares homology with calmodulin (CaM)-dependent protein kinase I, localizes principally within mitochondria, in particular at the outer mitochondrial membrane (Zhou et al. 2008) while others suggested an inner mitochondrial membrane localization (Silvestri et al. 2005, Gandhi et al. 2006) or a cytoplasmic pool (Weihofen et al. 2007, Haque et al. 2008). PINK1 seems to provide protection against oxidative stress (Valente et al. 2004, Yang et al. 2006). Its overexpression defends cell from mitochondrially-induced apoptosis caused by staurosporine, and from mitochondrial depolarization and apoptosis generated by the proteasomal inhibitor MG132 (Wood-Kaczmar et al. 2008). PINK1 is thought to interact with HTRA2 (Plun-Favreau et al. 2007), a mitochondrial serine protease, that is released from the mitochondrial intermembrane space into the cytosol, where it induces apoptotic cell death in addition to the permeabilization of the mitochondrial membrane leading to cytochrome c release (Suzuki et al. 2001, Hegde et al. 2002, Suzuki et al. 2004). Furthermore, recent studies suggest that PINK1 could act
INTRODUCTION in connection with Parkin, maybe controlling the balance between mitochondrial fission and fusion (Deng et al. 2008), and also with α-synuclein (Marongui et al. 2009). Parkin is located partially to the outer mitochondrial membrane (Darios et al. 2003) and also in the mitochondrial matrix. Parkin protects against oxidative stress and has a hypothesized role in mitochondrial gene transcription and biogenesis in proliferating cells, but the precise mechanism is unknown (Jiang et al. 2004). A recent study demonstrated a primary function for Parkin in the regulation of mitochondrial turnover. Actually, Parkin was shown to be specifically recruited to damaged or uncoupled mitochondria with low potential membrane to promote their clearance through the autophagosome (Narendra et al. 2008). Another PD and mitochondrial function related protein is DJ-1, which is mainly expressed in the cytosol, in the nucleus and in the mitochondria (a pool located in the mitochondrial intermembrane space and in the matrix). DJ-1 is thought to be neuroprotective (Abou-Sleiman et al. 2003, Zhang et al. 2005, Abeliovich and Flint Beal 2006, Zhou et al. 2006, Andres-Mateos et al. 2007, Schapira 2008) as it was recently reported to translocate to the mitochondria under conditions of oxidative stress (Junn et al. 2008). DJ-1 is then relocalized into the nucleus, where it is proposed to bind multiple RNAs and regulate p53‟s transcriptional activity. 37
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Universidade de Santiago de Compost
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Don Ramón Soto Otero y Doña Estef
Page 9 and 10: Acknowledgements The work of this t
Page 11 and 12: Abbreviations AA ascorbic acid AD A
Page 13: Abbreviations (continuation) PCC pr
Page 16 and 17: List of figures (continuation) Chap
Page 19 and 20: TABLE OF CONTENTS INTRODUCTION ....
Page 21: CHAPTER 3 Brain oxidative stress an
Page 25 and 26: INTRODUCTION PARKINSON’S DISEASE
Page 27 and 28: INTRODUCTION PD is found in all eth
Page 29 and 30: Bradykinesia INTRODUCTION Bradykine
Page 31 and 32: INTRODUCTION predate the occurrence
Page 33 and 34: Table 1: Differential diagnostic in
Page 35 and 36: INTRODUCTION Table 3: National Inst
Page 37 and 38: Figure 4: Dopamine catabolism (Mén
Page 39 and 40: The basal ganglia INTRODUCTION The
Page 41 and 42: The death of SNpc DAergic neurons I
Page 43 and 44: INTRODUCTION the dorsomedial part o
Page 45 and 46: INTRODUCTION characterized as are l
Page 47 and 48: INTRODUCTION (Olanow et al. 2004).
Page 49 and 50: Etiology and pathogenesis of PD INT
Page 51 and 52: Ageing INTRODUCTION Ageing remains
Page 53 and 54: INTRODUCTION The finding of MPTP to
Page 55 and 56: INTRODUCTION may clarify why many n
Page 57 and 58: Misfolding and aggregation of prote
Page 59: INTRODUCTION (E3) (Figure 18A). Los
Page 63 and 64: INTRODUCTION Oxidative damage happe
Page 65 and 66: DA metabolism as a source of ROS IN
Page 67 and 68: Contribution of oxidative and nitro
Page 69 and 70: Excitotoxicity INTRODUCTION Glutama
Page 71 and 72: INTRODUCTION al. 1996, Cicchetti et
Page 73 and 74: Experimental models of PD INTRODUCT
Page 75 and 76: INTRODUCTION induce selective DAerg
Page 77 and 78: ALUMINIUM General features INTRODUC
Page 79 and 80: INTRODUCTION Varying amounts of alu
Page 81 and 82: INTRODUCTION and antiperspirants co
Page 83 and 84: INTRODUCTION approximately 3% of al
Page 85 and 86: Excretion INTRODUCTION As insoluble
Page 87 and 88: INTRODUCTION 3.5 mg may be increase
Page 89 and 90: INTRODUCTION Oteiza 1999), non-iron
Page 91 and 92: Aluminium as a cell membrane menace
Page 93 and 94: INTRODUCTION mobilization of Ca 2+
Page 95: Aluminium impairs neurotransmission
Page 99 and 100: AIMS OF THE PRESENT THESIS The main
Page 101: OBJETIVOS
Page 104 and 105: OBJETIVOS 3) Evaluar de forma preci
Page 107: CHAPTER 1 Time-course of brain oxid
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CHAPTER 1 INTRODUCTION 86 6-OHDA (2
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CHAPTER 1 MATERIALS AND METHODS Che
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CHAPTER 1 followed by centrifugatio
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CHAPTER 1 RESULTS Effects of 6-OHDA
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CHAPTER 1 DISCUSSION 94 As shown by
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CHAPTER 1 strategies or to study th
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CHAPTER 1 Fig. 2 Changes in PCC in
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CHAPTER 2
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ABSTRACT CHAPTER 2 In the present w
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MATERIALS AND METHODS Chemicals CHA
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CHAPTER 2 atomization used were 1,5
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DISCUSSION CHAPTER 2 Aluminium ente
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Table 1. Graphite furnace programme
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CHAPTER 3 Brain oxidative stress an
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CHAPTER 3 INTRODUCTION 120 The huma
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CHAPTER 3 MATERIALS AND METHODS Che
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CHAPTER 3 1:15 for hippocampus and
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CHAPTER 3 initially incorporated to
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CHAPTER 3 RESULTS In vivo effects o
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CHAPTER 3 Effects of aluminium admi
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CHAPTER 3 DISCUSSION 132 Aluminium
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CHAPTER 3 hippocampus, showed simil
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CHAPTER 3 assume that the distinct
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CHAPTER 3 Fig. 1 Levels of TBARS (A
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CHAPTER 3 Fig. 2 Enzyme activity of
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CHAPTER 3 Fig. 3 Microphotographs s
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CHAPTER 3 Fig. 5 Levels of TBARS (A
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CHAPTER 3 Fig. 6 In vitro effects o
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SUMMARY
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SUMMARY values were attained at 48
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SUMMARY neurodegeneration in the DA
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CONCLUSIONS The results obtained in
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13) Aluminium does affect neither M
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RESUMEN RESUMEN Desde el punto de v
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RESUMEN zonas cerebrales excepto en
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CONCLUSIONES
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CONCLUSIONES Capítulo 2 4) La admi
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CONCLUSIONES 172 En base a las conc
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Publications as a direct result fro
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