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neurotransmission and ion-channel activity. This stress may be part of the normal homeostasis and aging of DA neurons, but could be exacerbated in the presence of an unfavorable imbalance. In addition, the array data suggest a disintegration of key cellular functions, such as mitochondria-associated energy metabolism, protein degradation, synaptic function, and cytoskeletal integrity, revealing a cellular state that is characterized by programmed cell death. However, despite this cellular demise, some genes linked to survival mechanisms were upregulated, indicating the activation of compensatory mechanisms. Finally, the lack or the relatively modest deregulation of genes important for the DA neuronal phenotype suggests that the DA neurotransmitter identity (including DA production) seems to be sustained even when the neurons are severely damaged. It appears that the gene expression profile of the DA neurons of late-stage Parkinson's disease is consistent with the view that Parkinson's disease is a complex disorder and that multiple

To date, whether miRNAs are also actively involved in the etiology or progression of neurodegenerative disorders remains uncertain. These small regulators clearly seem to be required for the survival of specific types of mature neurons in some model organisms; however, whether the loss of individual miRNAs can account for the drastic disease phenotypes remains to be determined. As many different cellular processes have been implicated in neurodegenerative disorders, the miRNAs involved in these pathways will obviously be found as misregulated in disease tissues. However, the degree to which their misregulation is causative in the diseases remains a pressing, but unanswered, question. Identification of causal links opens prospects for therapeutic intervention, perhaps by replacing missing miRNAs or blocking the activity of miRNAs that are overexpressed. Similarly, some miRNAs seem to have a neuroprotective role; therefore, they could potentially be used to prevent, or at least decelerate, the progressive loss of neurons in the diseased brain. These are tantalizing prospects that remain far from our grasp (Bushati & Cohen, 2008). Studies of miRNA in neurodegenerative diseases are emerging. Currently, both changes in the expression profiles of several miRNA and polymorphisms affecting the interactions between miRNAs and their targets are being addressed in various studies on neurodegenerative disease. It is difficult to determine if the changes in miRNA expression detected in the brains or cerebrospinal fluid (CSF) of patients are primary or secondary events, or both. Nevertheless early or late in the evolution of the disease, they may contribute to the pathogenesis of the observed lesions and neuronal loss. Unique patterns of miRNA expression in the CSF of particular neurodegenerative diseases may be useful as molecular biomarkers for disease diagnosis and, eventually, for the prediction of therapeutic responses. The identification of miRNAs that cause a specific pathology could open new therapeutic perspectives to block endogenous miRNAs or deliver exogenous miRNAs. To date either antisense oligonucleotides that are chemically modified (Meister, 2004) or expressed sequences corresponding to multiple miRNA seed targets (miRNA sponge) (Ebert, 2007) have been used as microRNA inhibitors. Delivery of these molecules to the central nervous system, while avoiding toxicities, may be the challenge of future research in this area. Furthermore, as specific nuclear or cytoplasmic protein accumulation causes the neuropathological manifestation in several neurodegenerative disorders, the identification of microRNAs that regulate the translation of these targets may represent the first step toward therapeutic applications. The second step might be the evaluation of the quantitative effects of specific amounts of "therapeutic" microRNAs on the proteome (Barbato, 2009).

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**14** 

**Brain Mitochondrial Dysfunction** 

Laura B. Valdez1, Manuel J. Bandez2, Ana Navarro2† and Alberto Boveris1

Parkinson's disease (PD) is an old-age neurodegenerative disease with a small but significant genetic risk. The prevalence of PD is of 0.3% in the whole population, affecting more than 1% of the humans over 60 years of age (de Lau & Breteler, 2006). Parkinson´s disease is characterized by the progressive loss of dopamine due to degeneration of dopaminergic neurons in the *substancia nigra, striatum* body and brain cortex. In addition, αsynuclein-positive Lewy bodies in brainstem and neocortex are consistently found at autopsy (Forno, 1996; Jellinger & Mizuno, 2003). Therefore, in patients with PD, movements,

Complex factors contribute to the appearance of PD but with a constant mitochondrial involvement and a decreased capacity to produce energy (ATP) in the affected brain areas (Shapira, 1998; Shapira, 2008). Mitochondrial dysfunction in the human frontal cortex is to

Both environmental chemicals and genetic susceptibility are thought to contribute to the etiology of sporadic PD (Nagatsu, 2002). Despite of familial PD was correlated with a series of genes mutations, the etiology of idiopathic PD, which accounts for more than 90% of PD, is still not fully understood. It is well documented that there is an epidemiological link between PD and individuals who lives and works in rural areas and who has been exposed to various

Although the etiopathogenesis of PD is still elusive, *post mortem* studies support the involvement of oxidative stress in neurons with an increased production of superoxide

herbicides and insecticides (Gorell et al. 1998; Ayala et al., 2007; Gomez et al., 2007).

sleep, autonomic functions and cognition become progressively impaired.

be considered a factor contributing to impaired cognition in PD.

**2. Environmental aspects and experimental models** 

**1. Introduction** 

**1.1 Clinical characteristics of Parkinson's disease** 

*1Laboratory of Free Radical Biology, School of Pharmacy and Biochemistry,* 

*2Department of Biochemistry and Molecular Biology, School of Medicine,* 

**and Complex I Syndrome in** 

**Parkinson´s Disease** 

*University of Buenos Aires,* 

*University of Cádiz,* 

*1Argentina 2Spain* 

