Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.3.2.19 (ubiquitin-protein ligase)
 799 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parkinson's Disease (PD) is a common neurodegenerative disorder that is characterized by the progressive loss of dopamine (DA) neurons. Accompanying the loss the of DA neurons is the accumulation of Lewy bodies and neurites, intracytoplasmic proteinaceous inclusions that contain alpha-synuclein, synphilin-1, components of the ubiquitin proteasomal pathway and parkin. Recent advances indicate that PD is due in some individuals to genetic mutations in alpha-synuclein, DJ-1, PINK-1, LRRK2, and parkin. Understanding the molecular mechanisms by which mutations in familial-linked genes cause PD holds great promise for unraveling the mechanisms by which DA neurons degenerate in PD. Parkin is E3-ubiquitin-protein ligase that ubiquitinates itself and promotes its own degradation. Familial associated mutations of parkin have impaired ubiquitin ligase function suggesting that this may be the cause of familial autosomal recessive PD. Parkin might be required for formation of Lewy bodies as Lewy bodies are absent in patients with parkin mutations. Parkin interacts with and ubiquitinates the alpha-synuclein interacting protein, synphilin-1. Formation of Lewy-body-like ubiquitin-positive cytosolic inclusions occurs upon coexpression of alpha-synuclein, synphilin-1 and parkin. Nitric oxide inhibits Parkin's E-3 ligase activity and its protective function by nitric oxide through S-nitrosylation both in vitro and in vivo. Nitrosative and oxidative stress link parkin function with the more common sporadic form of Parkinson's disease and the related alpha-synucleinopathy, DLBD. Development of new therapies for PD and other disorders associated with nitrosative and oxidative stress may follow the elucidation of the pathways by which NO S-nitrosylates and inhibits parkin. Moreover, parkin and alpha-synuclein are linked in common pathogenic mechanism through their interaction with synphilin-1 and parkin may be important for the formation of Lewy bodies.
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PMID:Parkin and defective ubiquitination in Parkinson's disease. 1701 31

These are really exciting times in the field of Parkinson's disease research. Although the etiology of sporadic disease still remains a mystery, many of the proteins associated with hereditary disease (5-10% of all disease) have now been identified. Only time will tell whether proteins associated with hereditary disease are involved in the development of sporadic disease. The most valuable proteomic studies performed to date are, and continue to be, those aimed at identifying endogenous binding partners, substrates, post-translational modifications and cellular pathways affected by these proteins. Similar to global proteomic approaches, even these approaches have surprisingly often been characterized by the production of very long lists of proteins. Consequently, the parallel development of more refined protein-protein interactions maps has aided the chance of identifying those protein complexes and/or cellular pathways, which, when disrupted, lead to the development of disease. The knowledge gained from these studies is essential, as targeting the activities of these proteins, or the pathways they operate in, currently offers the best opportunity to develop new therapeutic strategies to treat the disease. They may include agents to modulators of kinase activities (e.g., PINK1 and LRRK2), modulators of the activity of the ubiquitin-protein ligase, Parkin, proteostasis agents to block alpha-synuclein filament assembly and toxicity, or promote the refolding of mutant proteins, modulators of alpha-synuclein transfer between cells, reagents to regulate cargo dynamics along axonal microtubule networks, stimulators of autophagy and/or modulators of cellular stress pathways. The second major challenge will be to identify biomarkers to enable population screening to identify those with asymptomatic early-stage disease. Whether the analysis of blood or urine samples will yield such a marker, remains to be determined. Success or failure will be highly dependent on adopting strict standard operating procedures for the collection, processing and storage of samples, combined with the need for the identification of the most robust methods of prefractionation of samples to remove the most abundant proteins prior to proteomic screening.
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PMID:Understanding the molecular basis of Parkinson's disease, identification of biomarkers and routes to therapy. 2065 10