Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P62988 (Ubiquitin)
 4,326 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parkinson's disease (PD) is characterized pathologically by progressive neurodegeneration of the nigrostriatal dopamine (DA) system. Currently, the cause of the disease is unknown, except for a small percentage of familial cases (<10% of total). The rat rotenone model reproduces many of the pathological features of the human disease, including apomorphine-responsive behavioral deficits, DA depletion, loss of striatal DA terminals and nigral dopaminergic neurons, and alpha-synuclein/polyubiquitin-positive cytoplasmic inclusions reminiscent of Lewy bodies. Therefore, this model is well-suited to examine potential neuroprotective agents. Melatonin is produced mainly by the pineal gland and is known primarily for regulating circadian rhythms. It also has potent free radical scavenging and antiinflammatory properties. Melatonin has been reported to be neuroprotective in the 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models of PD. However, there are conflicting reports suggesting that melatonin does not provide neuroprotection in these models. Melatonin elicits significant functional changes in the nigrostriatal DA system that may affect 6-OHDA and MPTP entry into cells. Therefore, rotenone is an ideal model for assessing protection, because it does not rely on the dopamine transporter uptake to exert neurotoxicity. In this study, the neuroprotective potential of melatonin in the rotenone PD model was assessed. Melatonin potentiated striatal catecholamine depletion, striatal terminal loss, and nigral DA cell loss. Indeed, melatonin alone elicited alterations in striatal catecholamine content. Our findings indicate that melatonin is not neuroprotective in the rotenone model of PD and may exacerbate neurodegeneration.
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PMID:Melatonin treatment potentiates neurodegeneration in a rat rotenone Parkinson's disease model. 1968 Nov 69

RNA interference screen previously revealed that a HECT-domain E3 ubiquitin ligase, neuronal precursor cell expressed, developmentally down-regulated 4-2 (Nedd4-2), is necessary for ubiquitination and endocytosis of the dopamine transporter (DAT) induced by the activation of protein kinase C (PKC). To further confirm the role of Nedd4-2 in DAT ubiquitination and endocytosis, we demonstrated that the depletion of Nedd4-2 by two different small interfering RNA (siRNA) duplexes suppressed PKC-dependent ubiquitination and endocytosis of DAT in human and porcine cells, whereas knock-down of a highly homologous E3 ligase, Nedd4-1, had no effect on DAT. The abolished DAT ubiquitination in Nedd4-2-depleted cells was rescued by expression of recombinant Nedd4-2. Moreover, overexpression of Nedd4-2 resulted in increased PKC-dependent ubiquitination of DAT. Mutational inactivation of the HECT domain of Nedd4-2 inhibited DAT ubiquitination and endocytosis. Structure-function analysis of Nedd4-2-mediated DAT ubiquitination revealed that the intact WW4 domain and to a lesser extent WW3 domain are necessary for PKC-dependent DAT ubiquitination. Moreover, a fragment of the Nedd4-2 molecule containing WW3, WW4, and HECT domains was sufficient for fully potentiating PKC-dependent ubiquitination of DAT. Analysis of DAT ubiquitination using polyubiquitin chain-specific antibodies showed that DAT is mainly conjugated with Lys(63)-linked ubiquitin chains. siRNA analysis demonstrated that this polyubiquitination is mediated by Nedd4-2 cooperation with UBE2D and UBE2L3 E2 ubiquitin-conjugating enzymes. The model is proposed whereby each ubiquitinated DAT molecule is modified by a single four-ubiquitin Lys(63)-linked chain that can be conjugated to various lysine residues of DAT.
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PMID:Lysine 63-linked polyubiquitination of the dopamine transporter requires WW3 and WW4 domains of Nedd4-2 and UBE2D ubiquitin-conjugating enzymes. 2005 13