Genetics of Parkinson’s disease. J Neurol

Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Current Opinion in Neurology (Impact Factor: 5.31). 09/2005; 18(4):363-9. DOI: 10.1007/s004150170066
Source: PubMed


Parkinson's disease is the second most common neurodegenerative disorder and affects 2% of the population over the age of 60 years. Due to the increasing proportion of elderly individuals in developed countries, Parkinson's disease and related neurodegenerative disorders represent a growing burden on the health care system. In the majority of cases, the cause of the disease is still unknown, and its elucidation remains one of the major challenges of the neurosciences. Recent findings in rare genetic forms of Parkinson's disease have allowed the development of novel animal models, providing a basis for a better understanding of the molecular pathogenesis of the disease, setting the stage for the development of novel treatment strategies.
Several novel genes for monogenic forms of Parkinson's disease, such as PINK-1 for an autosomal-recessive early-onset variant, and LRRK2 for a relatively common late-onset autosomal-dominant form have recently been discovered, and several novel animal models have been generated on the basis of genes that had been found earlier.
The combination of genetic, pathologic and molecular findings provide increasing evidence that the pathways identified through the cloning of different disease genes are interacting on different levels and share several major pathogenic mechanisms.

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    • "It is characterized by death of dopaminergic neurons of the substantia nigra pars compacta (SNpc) of the brain [2] and by the presence of intracellular aggregated inclusions containing mainly α-synuclein (αSyn), called Lewy bodies (LB) [3], [4]. The disease can be divided into sporadic and early-onset familial PD; the latter is linked to three missense mutations, A53T, A30P and E46K, as well as multiple copies of the wild-type (wt) αSyn gene [5], [6], [7], [8]. Given that αSyn is the major component of LB in both familial and sporadic PD cases, it is considered a critical factor in PD aetiology [4]. "
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    ABSTRACT: Parkinson's disease (PD) is one of the most common neurodegenerative diseases. It is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. Another feature is represented by the formation in these cells of inclusions called Lewy bodies (LB), principally constituted by fibrillar α-synuclein (αSyn). This protein is considered a key element in the aetiology of a group of neurodegenerative disorders termed synucleinopathies, which include PD, but the cellular and molecular mechanisms involved are not completely clear. It is established that the inflammatory process plays a crucial role in the pathogenesis and/or progression of PD; moreover, it is known that aggregated αSyn, released by neurons, activates microglia cells to produce pro-inflammatory mediators, such as IL-1β. IL-1β is one of the strongest pro-inflammatory cytokines; it is produced as an inactive mediator, and its maturation and activation requires inflammasome activation. In particular, the NLRP3 inflammasome is activated by a wide variety of stimuli, among which are crystallized and particulate material. In this work, we investigated the possibility that IL-1β production, induced by fibrillar αSyn, is involved the inflammasome activation. We demonstrated the competence of monomeric and fibrillar αSyn to induce synthesis of IL-1β, through TLR2 interaction; we found that the secretion of the mature cytokine was a peculiarity of the fibrillated protein. Moreover, we observed that the secretion of IL-1β involves NLRP3 inflammasome activation. The latter relies on the phagocytosis of fibrillar αSyn, followed by increased ROS production and cathepsin B release into the cytosol. Taken together, our data support the notion that fibrillar αSyn, likely released by neuronal degeneration, acts as an endogenous trigger inducing a strong inflammatory response in PD.
    PLoS ONE 01/2013; 8(1):e55375. DOI:10.1371/journal.pone.0055375 · 3.23 Impact Factor
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    • "PD is associated with degeneration of dopaminergic neurons in the substantia nigra parts compacta. One of the pathological hallmarks of PD is the presence of intracellular inclusions called Lewy bodies that consist of aggregates of the presynaptic soluble called α-syneclein (Gasser 2001; Beal 1995). It is clear that the underlying factor in the neurological disorders is increased oxidative stress substantiated by the findings that the protein side chains are modified either directly by reactive oxygen species (ROS) or indirectly by the products of lipid peroxidation (Halliwell 1994). "
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    ABSTRACT: The increasing data provides enough evidences confirming the involvement of free radicals and other reactive oxygen species (ROS) superoxide radical (. O 2−), nitric oxide (NO. ), hydrogen peroxide (H2O2) and hydroxyl radicals (. OH) in a number of physiological and pathological processes. Imbalance between levels of ROS resulting in the body and the capacity of antioxidant defense mechanisms occur oxidative stress (OS). OS is related to a number of structural and functional damages to cells and is involved in the pathogenesis of many diseases, including neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease (PD), amyotrophic lateral sclerosis, and Huntington disease. Defects in oxidative phosphorylation and oxidative damage play an important role in neurodegenerative diseases. The aim of this study was to investigate some biomarkers of OS such as the level of lipid peroxidation measured as malondialdehyde (MDA) reactive products and activity of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) in the blood of PD patients compared with control group of healthy volunteers. By the present research we report higher levels of MDA products and an imbalance in SOD and CAT enzyme activities in PD patients compared to the control group.
    Comparative Clinical Pathology 03/2012; 22(2). DOI:10.1007/s00580-012-1407-8 · 0.37 Impact Factor
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    • "Both genetic and environmental factors can be implicated in its etiology. In the past decade, several genetic factors have been identified and five genes were conclusively implicated as causative of autosomal dominant (SNCA and LRRK2) or autosomal recessive (PARKIN, PINK1 and DJ-1) forms of PD [11]. ISSN 0278-0240/12/$27.50 "
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    ABSTRACT: Parkinson's disease is one of the most common neurodegenerative disorders associated with aging, reaching ∼ 2% of individuals over 65 years. Knowledge achieved in the last decade about the genetic basis of Parkinson's disease clearly shows that genetic factors play an important role in the etiology of this disorder. Exon dosage variations account for a high proportion of Parkinson's disease mutations, mainly for PARKIN gene. In the present study, we screened genomic rearrangements in SNCA, PARKIN, PINK1 and DJ-1 genes in 102 Brazilian Parkinson's disease patients with early onset (age of onset ⩽ 50 years), using the multiplex ligation-dependent probe amplification method. Family history was reported by 24 patients, while 78 were sporadic cases. Screening of exon dosage revealed PARKIN and PINK1 copy number variations, but no dosage alteration was found in SNCA and DJ-1 genes. Most of the carriers harbor heterozygous deletions or duplications in the PARKIN gene and only one patient was found to have a deletion in PINK1 exon 1. Data about dosage changes are scarce in the Brazilian population, which stresses the importance of including exon dosage analysis in Parkinson's disease genetic studies.
    Disease markers 02/2012; 32(3):173-8. DOI:10.3233/DMA-2011-0873 · 1.56 Impact Factor
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