Article

Genetics of Parkinson's disease

Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Current Opinion in Neurology (Impact Factor: 5.73). 09/2005; 18(4):363-9. DOI: 10.1007/s004150170066
Source: PubMed

ABSTRACT 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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    • "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
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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 · 2.17 Impact Factor
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    • "main cause of these motor symptoms is the progressive loss of the pigmented dopaminergic neurons of the substantia nigra (SN) pars compacta (Fahn 2003) which project to the striatum, whereas non-motor symptoms, such as hyposmia, sleep disorder, autonomic dysfunctions, depression and dementia mirror the progressive neuronal loss which starts from the enteric, autonomic and olfactory nervous systems via the brainstem to the cortex (Braak et al. 2003). While the molecular causes are currently unknown in most cases of old-age PD, the underlying genetic factors have been elucidated in some rare familial cases, usually with earlier disease onset (Gasser 2001; Huang et al. 2004). In the past 13 years, 16 genes or chromosomal loci (PARK1-16) have been linked to familial PD, commencing with the discovery of an A53T missense mutation in the alpha-synuclein gene (SNCA) (Polymeropoulos et al. 1997) and the later description of SNCA gene duplication and triplication events as the cause of autosomal dominant early-onset PD (Singleton et al. 2003). "
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    ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disorder frequent at old age characterized by atrophy of the nigrostriatal projection. Overexpression and A53T-mutation of the presynaptic, vesicle-associated chaperone alpha-synuclein are known to cause early-onset autosomal dominant PD. We previously generated mice with transgenic overexpression of human A53T-alpha-synuclein (A53T-SNCA) in dopaminergic substantia nigra neurons as a model of early PD. To elucidate the early and late effects of A53T-alpha-synuclein on the proteome of dopaminergic nerve terminals in the striatum, we now investigated expression profiles of young and old mice using two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) and mass spectrometry. In total, 15 proteins were upregulated and 2 downregulated. Mice before the onset of motor anomalies showed an upregulation of the spot containing 14-3-3 proteins, in particular the epsilon isoform, as well as altered levels of chaperones, vesicle trafficking and bioenergetics proteins. In old mice, the persistent upregulation of 14-3-3 proteins was aggravated by an increase of glial fibrillary acidic protein (GFAP) suggesting astrogliosis due to initial neurodegeneration. Independent immunoblots corroborated GFAP upregulation and 14-3-3 upregulation for the epsilon isoform, and also detected significant eta and gamma changes. Only for 14-3-3 epsilon a corresponding mRNA increase was observed in midbrain, suggesting it is transcribed in dopaminergic perikarya and accumulates as protein in presynapses, together with A53T-SNCA. 14-3-3 proteins associate with alpha-synuclein in vitro and in pathognomonic Lewy bodies of PD brains. They act as chaperones in signaling, dopamine synthesis and stress response. Thus, their early dysregulation probably reflects a response to alpha-synuclein toxicity.
    Journal of Neural Transmission 09/2011; 119(3):297-312. DOI:10.1007/s00702-011-0717-3 · 2.87 Impact Factor
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