Deletions in the Parkin gene and genetic heterogeneity in a Greek family with early onset Parkinson disease

ArticleinHuman Genetics 103(4):424-7 · November 1998with10 Reads
DOI: 10.1007/s004390050845 · Source: PubMed
Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease and is manifested as a movement disorder. A positive family history is the second most important risk factor for developing the illness, after age. Both autosomal dominant and recessive forms of the illness have been described. Recently deletions in a novel gene, parkin, have been associated with the autosomal recessive form of the illness in Japanese families. In this study, we demonstrate that deletions of exons 5, 6 and 7 of the parkin gene are present in two affected individuals of a Greek pedigree with early onset Parkinson's disease. However, no deletions were identified in a different branch of the same pedigree with three affected individuals. These results suggest that deletions in the parkin gene will be found in other families besides those of Japanese origin and that there must be at least one additional locus responsible for early onset autosomal recessive Parkinson's disease.
    • "One year later, the Shimizu group cloned the AR-JP gene, PARK2, and identified more Japanese AR-JP patients with either an exon 4 or a large-scale deletion between exons 3 and 7 (Kitada et al., 1998). Other patients of various ethnicities with early-onset PD were soon reported to also harbor PARK2 mutations with varying deletions or point mutations that cause PARK2 protein loss of function (Hattori et al., 1998a, 1998b; Leroy et al., 1998; Lü cking et al., 1998). PARK2 contains 12 exons that encode the 465 amino acid protein, Parkin (Kitada et al., 1998). "
    [Show abstract] [Hide abstract] ABSTRACT: Understanding the function of genes mutated in hereditary forms of Parkinson's disease yields insight into disease etiology and reveals new pathways in cell biology. Although mutations or variants in many genes increase the susceptibility to Parkinson's disease, only a handful of monogenic causes of parkinsonism have been identified. Biochemical and genetic studies reveal that the products of two genes that are mutated in autosomal recessive parkinsonism, PINK1 and Parkin, normally work together in the same pathway to govern mitochondrial quality control, bolstering previous evidence that mitochondrial damage is involved in Parkinson's disease. PINK1 accumulates on the outer membrane of damaged mitochondria, activates Parkin's E3 ubiquitin ligase activity, and recruits Parkin to the dysfunctional mitochondrion. Then, Parkin ubiquitinates outer mitochondrial membrane proteins to trigger selective autophagy. This review covers the normal functions that PINK1 and Parkin play within cells, their molecular mechanisms of action, and the pathophysiological consequences of their loss. Copyright © 2015 Elsevier Inc. All rights reserved.
    Article · Jan 2015
    • "Another possibility is that reduced mono-Ub levels as a result of UCHL1 perturbation inhibits the UPP more generally, which in turn impacts BACE1 stability. In relation to PD, a missense mutation in UCHL1 (I93M) was described in 1998 as the cause of dominantly-inherited PD in a family (Leroy et al., 1998). In in vitro reconstituted assays, UCHL1 I93M was found to have reduced DUB activity (Nishikawa et al., 2003), thus it was initially hypothesized that PD could be due to partial loss of UCHL1 activity. "
    [Show abstract] [Hide abstract] ABSTRACT: The Ubiquitin-Proteasome Pathway (UPP), which is critical for normal function in the nervous system and is implicated in various neurological diseases, requires the small modifier protein ubiquitin to accomplish its duty of selectively degrading short-lived, abnormal or misfolded proteins. Over the past decade, a large class of proteases collectively known as deubiquitinating enzymes (DUBs) has increasingly gained attention in all manners related to ubiquitin. By cleaving ubiquitin from another protein, DUBs ensure that the UPP functions properly. DUBs accomplish this task by processing newly translated ubiquitin so that it can be used for conjugation to substrate proteins, by regulating the “where, when, and why” of UPP substrate ubiquitination and subsequent degradation, and by recycling ubiquitin for re-use by the UPP. Because of the reliance of the UPP on DUB activities, it is not surprising that these proteases play important roles in the normal activities of the nervous system and in neurodegenerative diseases. In this review, we summarize recent advances in understanding the functions of DUBs in the nervous system. We focus on their role in the UPP, and make the argument that understanding the UPP from the perspective of DUBs can yield new insight into diseases that result from anomalous intra-cellular processes or inter-cellular networks. Lastly, we discuss the relevance of DUBs as therapeutic options for disorders of the nervous system.
    Full-text · Article · Aug 2014
    • "Therefore, one could say that early PD is usually genetically determined. In the last decades, there has been an increase in the number of PD family based studies [4,67,7273747576777879808182. Most of these show an autosomic pattern, either dominant or recessive . "
    [Show abstract] [Hide abstract] ABSTRACT: Neurodegenerative diseases are characterized by a progressive dysfunction of the nervous system. Often associated with atrophy of the affected central or peripheral nervous structures, they include diseases such as Parkinson's Disease (PD), Alzheimer's Disease and other dementias, Genetic Brain Disorders, Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease), Huntington's Disease, Prion Diseases, and others. The prevalence of neurodegenerative diseases has increased over the last years. This has had a major impact both on patients and their families and has exponentially increased the medical bill by hundreds of billions of Euros. Therefore, understanding the role of environmental and genetic factors in the pathogenesis of PD is crucial to develop preventive strategies. While some authors believe that PD is mainly genetic and that the aging of the society is the principal cause for this increase, different studies suggest that PD may be due to an increased exposure to environmental toxins. In this article we review epidemiological, sociological and experimental studies to determine which hypothesis is more plausible. Our conclusion is that, at least in idiopathic PD (iPD), the exposure to toxic environmental substances could play an important role in its aetiology.
    Full-text · Article · May 2014
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