The Genomic Structure and Promoter Region of the Human Parkin Gene
Parkin has been identified as a causative gene of the autosomal recessive juvenile parkinsonism (AR-JP). In this study, we determined the genomic structure of the Parkin gene and identified a core promoter region based on the DNA sequence of 1.4 Mb. The 5'-flanking region contained no apparent TATA or CAAT box elements but several putative cis-elements for various transcription factors. The GC- and CpG-rich regions were observed not only in the 5'-flanking sequence but also in the 5'-part of the first intron of Parkin. We identified an exact starting point of Parkin transcription. A core promoter region was determined by transfecting a series of deletion constructs with a dual luciferase reporter system into human neuroblastoma cells. Furthermore, we located a neighboring novel gene in a head-to-head direction with Parkin with only a 198-bp interval.
Available from: ncbi.nlm.nih.gov
- "The parkin gene is large , spanning over 1 . 4 Mega bases with 12 exons and large intronic regions ( Kitada et al . 1998 ; Kitada et al . 1999 ; Asakawa et al . 2001 ) . The gene encodes a ∼52kDa protein that is 465 amino acids in length ( Kitada et al . 1998 ) . The protein has an amino terminal ubiquitin - like ( Ubl ) domain as well as two Really - Interesting - New - Gene ( RING ) finger domains which are separated by an in - between - RING ( IBR ) finger domain at the carboxyl terminus ( Kitada"
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ABSTRACT: J. Neurochem. (2010) 113, 402–417.
Various mutations in the PARK2 gene which encodes the protein, parkin, are causal of a disease entity-termed autosomal recessive juvenile parkinsonism. Parkin can function as an E3 ubiquitin-protein ligase, mediating the ubiquitination of specific targeted proteins and resulting in proteasomal degradation. Parkin is thought to lead to parkinsonism as a consequence of a loss in its function. In this study, immunoblot analyses of brain extracts from Balb/c, C57BL/6, C3H, and 129S mouse strains demonstrated significant variations in immunoreactivity with anti-parkin monoclonal antibodies (PRK8, PRK28, and PRK109). This resulted partly from differences in the steady-state levels of parkin protein across mouse strains. There was also a complete loss of immunoreactivity for PRK8 and PRK28 antibodies in C3H mice due to was because of a homologous nucleotide mutation resulting in an E398Q amino acid substitution. In cultured cells, parkin harboring this mutation had a greater tendency to aggregate, exhibited reduced interaction with the E2 ubiquitin-conjugating enzymes, UbcH7 and UbcH8, and demonstrated loss-of-function in promoting the proteosomal degradation of a specific putative substrate, synphilin-1. In situ, C3H mice displayed age-dependent increased levels of brain cortical synphilin-1 compared with C57BL/6, suggesting that E398Q parkin in these mice is functionally impaired and that C3H mice may be a suitable model of parkin loss-of-function similar to patients with missense mutations.
Journal of Neurochemistry 04/2010; 113(2):402-17. DOI:10.1111/j.1471-4159.2010.06605.x · 4.28 Impact Factor
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ABSTRACT: The hypothesis that heredity plays an important role in the etiology of PD has long seemed attractive. It was initially suggested by positive family histories and later by reports of kindreds of "parkinsonism." It was reinforced by the first systematic family study of PD conducted a half-century ago by Mjones. However, closer study of the clinical data indicates that familial aggregations of parkinsonism have reflected various other disorders, notably OPCA and other forms of multiple system atrophy. Case control studies have failed to document a prevalence of PD among first-degree relatives of index cases significantly exceeding that found in control groups. More recently, the concordance rate for PD among monozygotic twins has been found to be unexpectedly low and not significantly different from that among dizygotic twins or the prevalence among first-degree relatives. Thus, the best available data do not support a role of heredity in the etiology of PD. A nonhereditary, possibly congenital genetic defect is, however, not excluded.
Science 12/1997; 278(5341):1212-3. DOI:10.1126/science.278.5341.1209d · 33.61 Impact Factor
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ABSTRACT: Mutations in the parkin gene cause autosomal recessive inherited juvenile parkinsonism (ARJP) and account for the majority of cases of inherited Parkinson's disease (PD) of young onset (<45 years of age). Patients with parkin mutations commonly have atypical clinical features such as dystonia at onset, hyper-reflexia, diurnal fluctuations, and sleep benefit; however, parkin mutation patients with both typical PD symptoms and older age of onset have been identified. Parkin is a ubiquitin protein ligase (E3), a component in the pathway that attaches ubiquitin to specific proteins, designating them for degradation by the proteasome. Several substrates for parkin have been identified (CDCrel-1, o-glycosylated alpha-synuclein, parkin associated endothelin-like cell receptor, and synphilin). The role of these substrates in the pathogenesis of ARJP is under active study. Most patients with parkin mutations lack Lewy bodies, suggesting that functional parkin is involved in the formation of these highly ubiquitinated inclusions. Furthermore, the recognition that parkin mutations can lead to a disorder clinically similar to sporadic PD, but presumably lacking Lewy bodies, calls into question the necessity of Lewy bodies for the diagnosis of PD and nigral cell death. Studies of parkin are increasing the focus on the role of the ubiquitin-proteasome system in the pathogenesis of both familial and sporadic PD.
Current Neurology and Neuroscience Reports 07/2002; 2(4):296-302. DOI:10.1007/s11910-002-0004-7 · 3.06 Impact Factor
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