Aberrant molecular properties shared by familial Parkinson's disease-associated mutant UCH-L1 and carbonyl-modified UCH-L1

Kabuta, Tomohiro; Setsuie, Rieko; Mitsui, Toshio; Kinugawa, Aiko; Sakurai, Mikako; Aoki, Shunsuke; Uchida, Kenko; Wãda, Keiji

doi:10.1093/hmg/ddn155

Human Molecular Genetics

2008

DOI: 10.1093/hmg/ddn155

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Aberrant molecular properties shared by familial Parkinson's disease-associated mutant UCH-L1 and carbonyl-modified UCH-L1

Tomohiro Kabuta¹,

Rieko Setsuie²,

Toshio Mitsui³

et al.

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Cited by 27 publications

(48 citation statements)

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“…2 Compared with wild-type (WT) UCH-L1, I93M UCH-L1 displays increased insolubility and levels of interactions with other proteins in mammalian cells, features that are characteristic of several neurodegenerative disease-linked mutants. 3 These findings suggest that the I93M mutation in UCH-L1 is a causative mutation for PD. Although the binding of I93M UCH-L1 to monoubiquitin as well as the hydrolase activity of I93M UCH-L1 are decreased compared with those of WT UCH-L1, 1,3,4 mice deficient in UCH-L1 do not display obvious dopaminergic cell loss.…”

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confidence: 88%

“…1). 3 Several missense mutations in the α-synuclein gene are also linked to dominant-inherited PD. 7-9 α-Synuclein is thought to be a major component of cytoplasmic inclusions called Lewy bodies in the brains of patients with sporadic PD.…”

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confidence: 99%

“…18 Thus, it is possible that the increases in our previous data showing that the HAE modification of Cys-90 of UCH-L1 promotes the interactions of UCH-L1 with multiple proteins. 3 The appearance of HNE-modified proteins in nigral neurons is associated with sporadic PD. 26,27 We have previously observed that cysteine residues in UCH-L1 are main targets for HNE-modification of UCH-L1.…”

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confidence: 99%

“…26,27 We have previously observed that cysteine residues in UCH-L1 are main targets for HNE-modification of UCH-L1. 3 UCH-L1 is modified by 10-100 μM HNE, whereas α-synuclein, which contains no cysteine residues, is not modified by 100 μM HNE in mammalian cells, 3 suggesting that, in mammalian cells, HNE reacts with proteins mainly via cysteine residues. It is possible that, in sporadic PD, cysteine residue-reactive carbonyl stresses such as HAE result in the accumulation of α-synuclein, not by direct modification of α-synuclein, but via reaction with UCH-L1.…”

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confidence: 99%

“…24,25 In mammalian cells, carbonylmodified UCH-L1 can be produced by reactions with 10-100 μM HAE or 2-alkenals, but not by 100-500 μM ketoaldehydes or 0.1-1 mM H 2 O 2 . 3 Furthermore, I93M UCH-L1 and carbonylmodified UCH-L1 display shared aberrant properties, 3 suggesting that carbonyl-modified UCH-L1 constitutes one of the causes of sporadic PD. Therefore, we tested the effects of carbonyl modification of UCH-L1 on the interaction of UCH-L1 with LAMP-2A and chaperones.…”

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confidence: 99%

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Insights into links between familial and sporadic Parkinson's disease: Physical relationship between UCH-L1 variants and chaperone-mediated autophagy

Kabuta¹,

Wada²

2008

Autophagy

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confidence: 88%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Insights into links between familial and sporadic Parkinson's disease: Physical relationship between UCH-L1 variants and chaperone-mediated autophagy

Kabuta¹,

Wada²

2008

Autophagy

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Heterogeneous expression and functional relevance of the ubiquitin carboxyl-terminal hydrolase L1 in melanoma

et al. 2013

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The expression of ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) is deregulated in human cancer cells with tumor inhibiting or promoting functions. Due to less knowledge on the role of UCHL1 in melanoma progression, the expression pattern and function of UCHL1 as well as the deregulated signaling pathways were characterized. A large number of melanoma cell lines, tissue microarrays of melanoma lesions and control tissues were analyzed for UCHL1 expression using PCR, Western blot and/ or immunohistochemistry. The analysis revealed that melanocyte cultures, 24 of 331 melanoma lesions, two of 18 short-term cultures and two of 19 melanoma cell lines tested, respectively, heterogeneously expressed UCHL1. The low frequency of UCHL1 expression in melanoma cells was due to gene silencing by promoter DNA hypermethylation. Using different transfection models an enzyme activity-dependent growth promoting function of UCHL1 via the activation of the mitogen-activated protein kinase signaling pathway was found in melanoma cells. Under oxygen stress a dose-dependent effect of UCHL1 was detected, which was mediated by a dynamic modification of the PI3K-Akt signaling. Thus, the aberrant UCHL1 expression in melanoma cells is linked to dynamic changes in growth properties and signal transduction cascades suggesting that UCHL1 provides a novel marker and/or therapeutic target at least for a subset of melanoma patients.Ubiquitination plays a key role in the post-translational modification of proteins and regulates in combination with phosphorylation and other post-translational alterations a number of cellular processes such as differentiation, proliferation, apoptosis and neoplastic transformation. The ubiquitination of proteins is controlled by so called deubiquitinating enzymes (DUB), which revert the binding between ubiquitin (ub) and their substrates, 1 protect proteins from proteasomal degradation and recycle ub-molecules of poly-ub chains. The DUB family is categorized into five different groups: (i) the ubiquitin carboxyl-terminal hydrolases (UCH), (ii) the ubiquitinspecific proteases (USP), (iii) the ovarial tumor proteases, (iv) the protein domain proteases of the Machado-Josef-disease and (v) the Jab1/MPN domain associated metalloproteinases. 2 The UCH family member UCHL1, also known as PGP9.5, GAD or PARK5, is a cysteine protease with a molecular weight of approximately 25 kDa. Next to its hydrolase activity UCHL1 also possesses ligase activity, 3,4 thereby the protein repertoire is multivalent regulated by its involvement in the cellular protein degradation and stabilization processes as well as in the homeostasis of the ub balance. Although UCHL1 is mainly expressed in neuronal and neuroendocrine tissues and represents about 2% of the total protein content of the brain, 3 it is also found in the tubule epithelium of the kidney, 5,6 in ovary 7 as well as in testis. 8 In neurodegenerative diseases such as Alzheimer's (AD) or Parkinson's disease (PD), an altered expression of UCHL1 could be indicated 9,10 suggesting that...

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Deubiquitinating enzymes in cellular signaling and disease regulation

et al. 2015

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Protein post-translational modification by ubiquitin represents a complex signaling system that regulates many cellular events including proteostasis to intercellular communications. Deubiquitinating enzymes (DUBs) that specifically disassemble Ub-chains or regulate ubiquitin homeostasis reside as a central component in ubiquitin signaling. Human genome encodes almost 100 DUBs and majority of them are not well characterized. Considerable progress has been made in the understanding of enzymatic mechanism; however, their cellular substrate specificity and regulation are largely unknown. Involvement of DUBs in disease regulation has been depicted since its discovery and several attempts have been made for evaluating DUBs as a drug target. In this review, we have updated briefly a new insight of DUBs activity, their cellular role, disease regulation, and therapeutic potential. V C 2015 IUBMB Life, 67(7): [544][545][546][547][548][549][550][551][552][553][554][555] 2015

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Aberrant molecular properties shared by familial Parkinson's disease-associated mutant UCH-L1 and carbonyl-modified UCH-L1

Cited by 27 publications

References 0 publications

Insights into links between familial and sporadic Parkinson's disease: Physical relationship between UCH-L1 variants and chaperone-mediated autophagy

Insights into links between familial and sporadic Parkinson's disease: Physical relationship between UCH-L1 variants and chaperone-mediated autophagy

Heterogeneous expression and functional relevance of the ubiquitin carboxyl-terminal hydrolase L1 in melanoma

Deubiquitinating enzymes in cellular signaling and disease regulation

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