Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants

Nishikawa, Kaori; Li, Hang; Kawamura, Ryuichi; Osaka, Hitoshi; Wang, Yu Lai; Hara, Yoko; Hirokawa, Takatsugu; Manago, Yoshimasa; Amano, Taiju; Нода, Мами; Aoki, Shunsuke; Wada, Keiji

doi:10.1016/s0006-291x(03)00555-2

Cited by 148 publications

(104 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It is also possible that GFP-C220S has affinity for another membrane-bound protein, for example, endogenous UCH-L1 M . This proposal is consistent with the fact that UCH-L1 forms homodimers in solution (26,41).…”

Section: Uch-l1 Is Associated With the Endoplasmic Reticular Membranesupporting

confidence: 89%

Membrane-associated farnesylated UCH-L1 promotes α-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease

Liu

Meray

Grammatopoulos³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

127

131

View full text Add to dashboard Cite

Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is linked to Parkinson's disease (PD) and memory and is selectively expressed in neurons at high levels. Its expression pattern suggests a function distinct from that of its widely expressed homolog UCH-L3. We report here that, in contrast to UCH-L3, UCH-L1 exists in a membrane-associated form (UCH-L1 M ) in addition to the commonly studied soluble form. C-terminal farnesylation promotes the association of UCH-L1 with cellular membranes, including the endoplasmic reticulum. The amount of UCH-L1 M in transfected cells is shown to correlate with the intracellular level of ␣-synuclein, a protein whose accumulation is associated with neurotoxicity and the development of PD. Reduction of UCH-L1 M in cell culture models of ␣-synuclein toxicity by treatment with a farnesyltransferase inhibitor (FTI-277) reduces ␣-synuclein levels and increases cell viability. Proteasome function is not affected by UCH-L1 M , suggesting that it may negatively regulate the lysosomal degradation of ␣-synuclein. Therefore, inhibition of UCH-L1 farnesylation may be a therapeutic strategy for slowing the progression of PD and related synucleinopathies.farnesylation ͉ synuclein

show abstract

Section: Uch-l1 Is Associated With the Endoplasmic Reticular Membranesupporting

confidence: 89%

Membrane-associated farnesylated UCH-L1 promotes α-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease

Liu

Meray

Grammatopoulos³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

127

131

View full text Add to dashboard Cite

show abstract

“…16,17,30,31 Accordingly, the present results raise intriguing possibilities for the management of these pathological conditions by modifying the expression of UCH-L1 and activity of the ubiquitin-proteasome pathway. 50 Using this strategy with trophic factors, 18,46 NAALADase inhibitor, 17 glutamate transporter activators, such as bromocryptine, 51,52 or overexpression of GLAST or GLT-1, 16 may induce synergic effects on multiple cellular targets to prevent ischemia-induced neural cell apoptosis. However, due to the central function of the ubiquitin system in many basic cellular processes, modulation of this system can become a "double-edged sword".…”

Section: Discussionmentioning

confidence: 99%

Role of Ubiquitin Carboxy Terminal Hydrolase-L1 in Neural Cell Apoptosis Induced by Ischemic Retinal Injury in Vivo

Harada¹,

Harada²,

Wang³

et al. 2004

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

Ubiquitin is thought to be a stress protein that plays an important role in protecting cells under stress conditions; however, its precise role is unclear. Ubiquitin expression level is controlled by the balance of ubiquitinating and deubiquitinating enzymes. To investigate the function of deubiquitinating enzymes on ischemia-induced neural cell apoptosis in vivo, we analyzed gracile axonal dystrophy (gad) mice with an exon deletion for ubiquitin carboxy terminal hydrolase-L1 (UCH-L1), a neuron-specific deubiquitinating enzyme. In wild-type mouse retina, light stimuli and ischemic retinal injury induced strong ubiquitin expression in the inner retina, and its expression pattern was similar to that of UCH-L1. On the other hand, gad mice showed reduced ubiquitin induction after light stimuli and ischemia, whereas expression levels of antiapoptotic (Bcl-2 and XIAP) and prosurvival (brain-derived neurotrophic factor) proteins that are normally degraded by an ubiquitin-proteasome pathway were significantly higher. Consistently, ischemia-induced caspase activity and neural cell apoptosis were suppressed ϳ70% in gad mice. These results demonstrate that UCH-L1 is involved in ubiquitin expression after stress stimuli, but excessive ubiquitin induction following ischemic injury may rather lead to neural cell apoptosis in vivo. The small 76 amino acid protein ubiquitin plays a critical role in many cellular processes, including cell cycle control, transcriptional regulation, and synaptic development.

show abstract

“…However, we and others have shown that S-nitrosylation and further oxidation of parkin, a ubiquitin E3 ligase, or UCH-L1, a deubiquitinating enzyme that recycles ubiquitin, results in dysfunction of these enzymes and thus of the UPS. 17,20,[68][69][70][71] We found that nitrosative stress triggers S-nitrosylation of parkin (forming SNO-parkin) not only in rodent models of PD but also in the brains of human patients with PD and Lewy bodies. SNO-parkin initially stimulates ubiquitin E3 ligase activity, resulting in enhanced ubiquitination, as observed in Lewy bodies, followed by a decrease in enzyme activity, producing a futile cycle of dysfunctional UPS (Figure 2).…”

Section: S-nitrosylation As a Potential Positive Regulator Of Excitotmentioning

confidence: 99%

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

Nakamura

Lipton

2007

Cell Death Differ

View full text Add to dashboard Cite

Although activation of glutamate receptors is essential for normal brain function, excessive activity leads to a form of neurotoxicity known as excitotoxicity. Key mediators of excitotoxic damage include overactivation of N-methyl-D-aspartate (NMDA) receptors, resulting in excessive Ca 2 þ influx with production of free radicals and other injurious pathways. Overproduction of free radical nitric oxide (NO) contributes to acute and chronic neurodegenerative disorders. NO can react with cysteine thiol groups to form S-nitrosothiols and thus change protein function. S-nitrosylation can result in neuroprotective or neurodestructive consequences depending on the protein involved. Many neurodegenerative diseases manifest conformational changes in proteins that result in misfolding and aggregation. Our recent studies have linked nitrosative stress to protein misfolding and neuronal cell death. Molecular chaperones -such as protein-disulfide isomerase, glucose-regulated protein 78, and heat-shock proteins -can provide neuroprotection by facilitating proper protein folding. Here, we review the effect of S-nitrosylation on protein function under excitotoxic conditions, and present evidence that NO contributes to degenerative conditions by S-nitrosylating-specific chaperones that would otherwise prevent accumulation of misfolded proteins and neuronal cell death. In contrast, we also review therapeutics that can abrogate excitotoxic damage by preventing excessive NMDA receptor activity, in part via S-nitrosylation of this receptor to curtail excessive activity.

show abstract

Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants

Cited by 148 publications

References 48 publications

Membrane-associated farnesylated UCH-L1 promotes α-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease

Membrane-associated farnesylated UCH-L1 promotes α-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease

Role of Ubiquitin Carboxy Terminal Hydrolase-L1 in Neural Cell Apoptosis Induced by Ischemic Retinal Injury in Vivo

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

Contact Info

Product

Resources

About