Genes and Oxidative Stress in Sporadic and Familial Parkinsonism cDNA Microarray Studies

E. Grunblatt, S. Mandel, P. Riederer, and M.B.H. Youdim INTRODUCTION

In several neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), prion disease and their models, oxidative stress (OS) mechanisms are thought to be involved, resulting in the generation of reactive oxygen species (ROS), as well as glutamate receptor abnormalities, ubiquitin-proteasome dysfunction, inflammatory and cytokine activation, dysfunction in neurotrophic factors, damage to mitochondria, cytoskeletal abnormalities, synaptic dysfunction and activation of apoptosis pathways (1-4). In many animal models, in vitro and cell culture models, studies showed association between OS and microglia mediation of neuronal damage such as in PD models with 6-hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), cerebral ischemia, methamphetamine or transgenic animals (5-9). The evidences that OS may be an important culprit in the manifestations of neurodegeneration are still under investigation, but should be taken seriously for possible drug development and drug therapy. In order to investigate these hypotheses, many researchers have employed biochemical and protein analysis that provided a very small insight into the knowledge of OS involvement in many cascades of events leading to cell death. Therefore, nowadays many researchers use molecular biology techniques to investigate a much unexplored field on neuronal cell death in these diseases. The central genetic dogma states that genomic DNA is first transcribed into mRNA, after which mRNA is translated into protein. Proteins are critical to a wide range of intra- and extracellular activities, including enzymatic, regulatory and structural function. Estimates suggest that 50% of human transcriptome, the collection of mRNA in a cell, is expressed in the brain. Changes in mRNA expression can, but not always, result in phenotypical and morphological differences. Alterations in patterns of expression of multiple genes can offer new data concerning regulatory mechanisms and biochemical pathways; therefore, study of mRNA patterns in neurodegenerative disease may reveal mechanisms of OS involvement as well as others. For measuring gene expression at the level of mRNA, one can use several methods such as northern blot, polymerase chain reaction (PCR) after reverse transcription (RT), nuclease protection, cDNA sequencing, clone hybridization, differential display (DD), serial analysis of gene expression (SAGE) and microarray technology. These methods characterize global gene expression profiles and screen for significant differences in mRNA abundance (10).

Oxidative Stress and Neurodegenerative Disorders Edited by G. Ali Qureshi and S. Hassan Parvez

© 2007 Elsevier B.V. All rights reserved.

In the past five years, the transcriptomics and proteomics have become the most preferred methods for large-scale gene expression assessment after DD and SAGE techniques that provide in addition to known genes also novel unknown genes, but are laborious methods when compared to the microarrays. These global gene expression studies were laboured to understanding the mechanisms of neuronal cell death in many diseases such as PD, AD, ALS and prion disease. In many of these studies, common mechanisms causing neurodegeneration were revealed, such as neuroinflammatory cascades, oxidant as well as antioxidant proteins, apoptotic and antiapoptotic cascades, neuronal differentiation, synap-tic trafficking mechanisms, transcription signalling and ubiquitin-proteasomal cascades, in post-mortem tissues of patients with these neurodegenerative disorders in addition to brain areas of animal models and in neuronal cell culture (11). In this review, we will present the recent findings of gene expression profiling in PD animal models, cell culture and post-mortem sporadic PD subjects substantia nigra pars compact (SNpc), where the dopamine neurons degenerate. We will compare the findings in the different models as well as compare it to the recent findings in human patients.

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