To a large extent, biomedical research on Parkinson’s disease focuses onin vitroandin vivodisease models, as well as studies of postmortem brain

To a large extent, biomedical research on Parkinson’s disease focuses onin vitroandin vivodisease models, as well as studies of postmortem brain. death and survival. In addition, genes for neurotransmitter and ion channel receptors were also deregulated, supporting the view that alterations in electrical activity might influence DA neuron function. Our data provide a molecular fingerprint identity of latestage Parkinson’s disease DA neurons that will advance our understanding of the molecular pathology of this disease. Keywords:Parkinson’s disease, microarray, laser microdissection, pathogenesis, dopamine == Introduction == Parkinson’s disease is a neurodegenerative disorder caused by a progressive deterioration of midbrain dopamine (DA) neurons in the substantia nigra pars compacta (SNc). The death of DA cells is associated with tremor and rigidity and results in a gradual dysfunction of the extrapyramidal motor system. The disease affects about 23% of individuals over the age of 65 years and there is evidence that its prevalence is higher in the (±)-ANAP male population (Cantuti-Castelvetriet al.,2007). There is currently no cure for Parkinson’s disease and the underlying pathogenesis of the disease is still unknown. Two forms of Parkinson’s disease are recognized: a familial or early-onset Parkinson’s disease (<10% of all patients) and an idiopathic or late-onset Parkinson's disease (>85% of all cases) that does not appear to exhibit heritability. Overall, the pathology of Parkinson’s disease is complex and is most likely a consequence of an unspecified combination of genetic and environmental factors, which induce (±)-ANAP a common pathogenic cascade of molecular events (Maguire-Zeiss and Federoff,2003; Miller and Federoff,2005). Since the first description of this syndrome in 1817 by James Parkinson, Parkinson’s disease has been the subject of intense investigation to understand its pathophysiology and to develop therapeutic interventions. So far, pharmacological and surgical therapies are available and can alleviate some of the symptoms, but these interventions (±)-ANAP are associated with serious side effects and generally lose efficacy over time (Benabid,2007; Schapira,2007). Although research has progressed, one of the main hurdles for the development of therapeutic or preventative measures is the still limited understanding of the underlying pathophysiology of Parkinson’s disease and the lack of reliable biomarkers. To a large extent, biomedical research on Parkinson’s disease focuses onin vitroandin vivodisease models, as well as studies of postmortem brain. Based on the availability of more sophisticated technologies, the latter has become more prominent over the past years and has revealed novel insights in the pathogenesis of Parkinson’s disease. For example, several studies have used microarray technologies on the substantia nigra of normal control and Parkinson’s disease patients to assess differential gene expression profiles; data from these studies have helped to further delineate some disease-associated pathways (Grunblattet al.,2004; Hauseret al.,2005; Zhanget al.,2005; Dukeet al.,2006; Milleret al.,2006; Moranet al.,2006,2007; Moran and Graeber,2008). However, the array results in these studies did not entirely represent the DA neuronal profile, since large amounts of other Eno2 cell populations were also included in the dissected tissue. The introduction of laser microdissection (LMD) has further refined this approach and was essential to the demonstration of a broad gender-linked difference in the gene expression profile of human substantia nigra DA neurons (Cantuti-Castelvetriet al.,2007). In (±)-ANAP the current study, we used LMD (Beneset al.,2007) to isolate DA neurons from the substantia nigra of nine normal and 10 idiopathic Parkinson’s disease patients. Using microarray-based gene expression profiling, we have analysed our data based on cluster analyses of biological functions and cellular pathways relevant to Parkinson’s disease pathology and have compared the results to the published expression profiles. Our data confirm the involvement of several known molecular regulatory pathways in the pathogenesis of Parkinson’s disease: these include oxidative stress-induced cell responses and dysfunction of the mitochondrial and ubiquitin-proteasome system (UPS). In particular, we found clusters of differentially expressed genes that appear to be involved in extrinsic and intrinsic signalling (±)-ANAP events in programmed cell death (PCD), as well as a prominent down-regulation of multiple members of the PARK gene family, which are associated with familial forms of Parkinson’s disease. In addition, we have also noted changes in the expression of neurotransmitter.