UCHL‐1 is not a Parkinson's disease susceptibility gene

Healy, DG; Abou‐Sleiman, Patrick M.; Casas, JP; Ahmadi, KR; Lynch, Timothy; Gandhi, Sonia; Muqit, Miratul M. K.; Foltynie, Thomas; Barker, Roger A.; Bhatia, KP; Quinn, NP; Lees, Andrew J.; Gibson, J. M.; Holton, JL; Révész, Tamás; Goldstein, DB; Wood, Nicholas W.

doi:10.1002/ana.20757

Cited by 104 publications

(72 citation statements)

References 26 publications

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“…Subsequent studies failed to replicate the ILE93-MET variant in familial and sporadic forms of Parkinson disease and identified only one other common UCHL1 variant, a serine to tyrosine (SER18TYR) polymorphism (20,21). Although a protective effect for the UCHL1 SER18TYR variant against Parkinson disease was initially suggested, several subsequent association studies yielded conflicting results (22)(23)(24). In the family presented here, neither the patients homozygous for the UCHL1 GLU7ALA variant nor their heterozygous parents or siblings exhibited Parkinsonian features on neurological examination.…”

Section: Discussionmentioning

confidence: 99%

Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration

Bilgüvar

Tyagi

Özkara³

et al. 2013

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

167

142

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Ubiquitin C-terminal hydrolase-L1 (UCHL1), a neuron-specific deubiquitinating enzyme, is one of the most abundant proteins in the brain. We describe three siblings from a consanguineous union with a previously unreported early-onset progressive neurodegenerative syndrome featuring childhood onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfuction, and spasticity with upper motor neuron dysfunction. Through homozygosity mapping of the affected individuals followed by whole-exome sequencing of the index case, we identified a previously undescribed homozygous missense mutation within the ubiquitin binding domain of UCHL1 (UCHL1 GLU7ALA ), shared by all affected subjects. As demonstrated by isothermal titration calorimetry, purified UCHL1 GLU7ALA , compared with WT, exhibited at least sevenfold reduced affinity for ubiquitin. In vitro, the mutation led to a near complete loss of UCHL1 hydrolase activity. The GLU7ALA variant is predicted to interfere with the substrate binding by restricting the proper positioning of the substrate for tunneling underneath the cross-over loop spanning the catalytic cleft of UCHL1. This interference with substrate binding, combined with near complete loss of hydrolase activity, resulted in a >100-fold reduction in the efficiency of UCHL1 GLU7ALA relative to WT. These findings demonstrate a broad requirement of UCHL1 in the maintenance of the nervous system. protein quality control | recessive inherited neurodegeneration

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Section: Discussionmentioning

confidence: 99%

Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration

Bilgüvar

Tyagi

Özkara³

et al. 2013

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

167

142

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“…UCH-L1 has also been identified as a component of several inclusion bodies characteristic of neurodegenerative diseases including Lewy bodies (14). A polymorphism in the UCH-L1 gene, resulting in an S18Y substitution at the amino acid residue level, has been reported to be associated with decreased risk of PD in certain populations but not in other populations (15,16). We have also reported that UCH-L1 I93M and carbonyl-modified UCH-L1, which is associated with sporadic PD (17), display shared aberrant properties (13), suggesting that carbonyl-modified UCH-L1 constitutes one of the causes of sporadic PD.…”

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confidence: 99%

Aberrant Interaction between Parkinson Disease-associated Mutant UCH-L1 and the Lysosomal Receptor for Chaperone-mediated Autophagy

Kabuta

Furuta

Aoki

et al. 2008

Journal of Biological Chemistry

208

186

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Parkinson disease (PD) is the most common neurodegenerative movement disorder. An increase in the amount of ␣-synuclein protein could constitute a cause of PD. ␣-Synuclein is degraded at least partly by chaperone-mediated autophagy (CMA). The I93M mutation in ubiquitin C-terminal hydrolase L1 (UCH-L1) is associated with familial PD. However, the relationship between ␣-synuclein and UCH-L1 in the pathogenesis of PD has remained largely unclear. In this study, we found that UCH-L1 physically interacts with LAMP-2A, the lysosomal receptor for CMA, and Hsc70 and Hsp90, which can function as components of the CMA pathway. These interactions were abnormally enhanced by the I93M mutation and were independent of the monoubiquitin binding of UCH-L1. In a cell-free system, UCH-L1 directly interacted with the cytosolic region of LAMP-2A. Expression of I93M UCH-L1 in cells induced the CMA inhibition-associated increase in the amount of ␣-synuclein. Our findings may provide novel insights into the molecular links between ␣-synuclein and UCH-L1 and suggest that aberrant interaction of mutant UCH-L1 with CMA machinery, at least partly, underlies the pathogenesis of PD associated with I93M UCH-L1. Parkinson disease (PD)4 is the most common neurodegenerative movement disorder characterized by progressive degeneration confined mostly to dopaminergic neurons in the substantia nigra pars compacta. Although the majority of PD cases occur sporadically, nine genes have been reported to be associated with familial forms of PD. Several missense mutations in the ␣-synuclein gene are linked to dominantly inherited PD (1-3). Duplication and triplication of the ␣-synuclein gene were also shown to cause familial PD or parkinsonism (4 -6), indicating that increases in the levels of ␣-synuclein could constitute a cause of PD. ␣-Synuclein is a major component of cytoplasmic inclusions called Lewy bodies in the brains of patients with sporadic PD (7,8). These findings raised the idea that ␣-synuclein plays a central role in the pathogenesis of PD. Therefore, elucidating the molecular relationships between ␣-synuclein and other familial PD-associated proteins is important for understanding the mechanisms that underlie the pathology of PD.A missense mutation in the ubiquitin C-terminal hydrolase L1 (UCH-L1) gene, leading to an I93M substitution at the protein level, has been reported in two affected siblings of a German family with dominantly inherited PD (9). In this family, four of seven family members were affected with PD. However, the family members, except the two siblings, were not genotyped. There was an unaffected presumed carrier of the I93M mutation in the family. Therefore, the link between the I93M mutation and the development of PD has been questioned (10, 11). To clarify the link between the mutation and PD, we have generated UCH-L1 I93M transgenic mice and reported that these mice exhibit progressive dopaminergic cell loss (12). In addition, we have shown that, compared with UCH-L1 WT , UCH-L1 I93M exhibits increased insolubility a...

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“…Maraganore et al [8] found an inverse association between the UCH-L1 S18Y variant and PD in a sample of combined Asian and white participants. Two years later, Healy et al [10] conducted a meta-analyses of 9 case-control studies in white individuals and did not find a protective effect of the UCH-L1 gene in PD. A recent meta-analysis performed by Ragland et al [9] showed a statistically significant association between the S18Y variant and reduced risk of PD in Asian populations in a recessive model (YY vs. SY + SS, p = 0.0006).…”

Section: Discussionmentioning

confidence: 99%

“…The Ser 18 Tyr (S18Y; C54A) polymorphism in exon 3 has also been reported as a potential candidate [7], but its association with PD remains controversial. Some studies found a protective effect of the S18Y polymorphism on PD [8,9], whereas other studies detected no association between S18Y and PD [10]. Recently, Miyake et al [11] performed studies in a Japanese population and revealed that the UCH-L1 S18Y variant is a risk factor for sporadic PD.…”

Section: Introductionmentioning

confidence: 99%

UCH-L1 S18Y Variant and Risk of Parkinson's Disease in Asian Populations: An Updated Meta-Analysis

Zhu

Zhu²,

Liu³

et al. 2014

Neurodegener Dis

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The ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) gene has been implicated in the etiology of Parkinson's disease (PD). Several studies have evaluated the association between the UCH-L1 S18Y variant and the risk of PD. However, conflicting results have been reported. Therefore, we performed a meta-analysis to explore whether the UCH-L1 S18Y variant is associated with susceptibility to PD in Asians. A database search in Web of Science, MEDLINE, Embase and PubMed up to March 2014 identified 10 studies comprising 4,897 PD patients and 4,446 controls in total, which were included in this meta-analysis. In an updated meta-analysis, no significant associations between the S18Y polymorphism and PD in Asians were observed in recessive [p = 0.28, odds ratio (OR) = 1.47, 95% confidence interval (CI): 0.86-1.04] or dominant models (p = 0.46, OR = 0.96, 95% CI: 0.88-1.06). In the subgroup analysis by ethnicity, still no significant association was detected in dominant (for Chinese, OR = 0.97, 95% CI: 0.85-1.10; for Japanese, OR = 0.96, 95% CI: 0.83-1.11) and recessive models (for Chinese, OR = 0.99, 95% CI: 0.88-1.11; for Japanese, OR = 0.89, 95% CI: 0.76-1.04). The results of this meta-analysis suggested that the UCHL-1 S18Y polymorphism was not associated with the risk of PD in Asians. To our knowledge, this is the latest and largest meta-analysis assessing the association of the UCHL-1 S18Y variant with the risk of PD in Asian ancestry.

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UCHL‐1 is not a Parkinson's disease susceptibility gene

Abstract: Based on the current evidence, the UCHL-1 gene does not exhibit a protective effect in PD.

Cited by 104 publications

References 26 publications

Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration

Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration

Aberrant Interaction between Parkinson Disease-associated Mutant UCH-L1 and the Lysosomal Receptor for Chaperone-mediated Autophagy

<b><i>UCH-L1</i></b> S18Y Variant and Risk of Parkinson's Disease in Asian Populations: An Updated Meta-Analysis

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