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.
"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, UCHL1I93M 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.
"Intriguingly, parkin undergoes autoubiquitination in an E2-dependent manner, leading to its own degradation (Um and Chung 2006; Lim et al. 2005; Choi et al. 2000). Mutations in the PARK2 gene are the most common autosomal recessive cause of early-onset PD and typically not associated with a-synuclein and ubiquitin-positive LBs (Kitada et al. 1998; Abbas et al. 1999; Hattori et al. 1998; Leroy et al. 1998). However, parkin immunoreactivity was present in the central core of a majority of LBs from sporadic and non-parkin familial PD cases, suggesting that parkin is a key factor in the biogenesis of LB inclusions (van de Warrenburg et al. 2001; Schlossmacher et al. 2002; Shimura et al. 2000; Bandopadhyay et al. 2005). "
[Show abstract][Hide abstract] ABSTRACT: Parkinson's disease (PD) is one of the most common degenerative disorders of the central nervous system that produces motor and non-motor symptoms. The majority of cases are idiopathic and characterized by the presence of Lewy bodies containing fibrillar α-synuclein. Small ubiquitin-related modifier (SUMO) immunoreactivity was observed among others in cases with PD. Key disease-associated proteins are SUMO-modified, linking this posttranslational modification to neurodegeneration. SUMOylation and SUMO-mediated mechanisms have been intensively studied in recent years, revealing nuclear and extranuclear functions for SUMO in a variety of cellular processes, including the regulation of transcriptional activity, modulation of signal transduction pathways, and response to cellular stress. This points to a role for SUMO more than just an antagonist to ubiquitin and proteasomal degradation. The identification of risk and age-at-onset gene loci was a breakthrough in PD and promoted the understanding of molecular mechanisms in the pathology. PD has been increasingly linked with mitochondrial dysfunction and impaired mitochondrial quality control. Interestingly, SUMO is involved in many of these processes and up-regulated in response to cellular stress, further emphasizing the importance of SUMOylation in physiology and disease.
Neuromolecular medicine 08/2013; 15(4). DOI:10.1007/s12017-013-8259-5 · 3.68 Impact Factor
"These investigations have focused either on post-translational modifications of aSyn  or on mechanisms of degradation. Initially, a key role had been postulated for the ubiquitin proteasome pathway (UPP) in the degradation of aSyn, because mutations in two UPP-related genes, Parkin and UchL-1 have been shown to influence PD risk [15-18] and because molecular, cellular and animal studies linked these genes to UPP-dependent processing of aSyn [19-21]. However, growing evidence has indicated that the lysosome, as well as the proteasome, can mediate degradation of aSyn [22,23]. "
[Show abstract][Hide abstract] ABSTRACT: Elevated SNCA gene expression and intracellular accumulation of the encoded alpha-synuclein (aSyn) protein are associated with the development of Parkinson disease (PD). To date, few enzymes have been examined for their ability to degrade aSyn. Here, we explore the effects of CTSD gene expression, which encodes the lysosomal protease cathepsin D (CathD), on aSyn processing.
Over-expression of human CTSD cDNA in dopaminergic MES23.5 cell cultures induced the marked proteolysis of exogenously expressed aSyn proteins in a dose-dependent manner. Unexpectedly, brain extractions, Western blotting and ELISA quantification revealed evidence for reduced levels of soluble endogenous aSyn in ctsd knock-out mice. However, these CathD-deficient mice also contained elevated levels of insoluble, oligomeric aSyn species, as detected by formic acid extraction. In accordance, immunohistochemical studies of ctsd-mutant brain from mice, sheep and humans revealed selective synucleinopathy-like changes that varied slightly among the three species. These changes included intracellular aSyn accumulation and formation of ubiquitin-positive inclusions. Furthermore, using an established Drosophila model of human synucleinopathy, we observed markedly enhanced retinal toxicity in ctsd-null flies.
We conclude from these complementary investigations that: one, CathD can effectively degrade excess aSyn in dopaminergic cells; two, ctsd gene mutations result in a lysosomal storage disorder that includes microscopic and biochemical evidence of aSyn misprocessing; and three, CathD deficiency facilitates aSyn toxicity. We therefore postulate that CathD promotes 'synucleinase' activity, and that enhancing its function may lower aSyn concentrations in vivo.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.