Synaptic defects in ataxia mice result from a mutation in Usp14, encoding a ubiquitin-specific protease

Wilson, Scott; Bhattacharyya, Budhaditya; Rachel, Rivka A.; Coppola, Vincenzo; Tessarollo, Lino; Householder, Deborah B.; Fletcher, Colin; Miller, Richard J.; Copeland, Neal G.; Jenkins, Nancy A.

doi:10.1038/ng1006

Cited by 246 publications

(263 citation statements)

References 27 publications

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“…7 USP14 (ubiquitin-specific protease 14), located at 18p11.32, may be an interesting gene in the context of growth retardation and seizures as mice with a mutation resulting in reduced protein expression were growthretarded 20 and the protein has been implicated in regulating synaptic activity in mammals. 33 A second possible candidate gene for seizures, DLGAP1 (discs large-associated protein 1) located at 18p11.31, is part of the postsynaptic density in neuronal cells. 34 The hydrocephalus internus with brain atrophy present in cases 2 and 3 points to the localisation of a responsible haploinsufficient gene in the distal 8 Mb of 18p.…”

Section: Discussionmentioning

confidence: 99%

Towards mapping phenotypical traits in 18p− syndrome by array-based comparative genomic hybridisation and fluorescent in situ hybridisation

et al. 2006

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Molecular karyotyping holds the promise of improving genotype -phenotype correlations for frequent chromosome conditions such as the 18pÀ syndrome. In spite of more than 150 reported cases with deletions in 18p, no reliable phenotype map for the characteristic clinical findings such as mental retardation, post-natal growth retardation and typical facial features has been established yet. Here, we report on four patients with partial monosomy 18p of different sizes owing to unbalanced translocations that were thoroughly characterised clinically and by molecular karyotyping. One patient had a terminal deletion of 1.6 Mb in 18p and a trisomy of 8q24.23-qter as determined by array-based comparative genomic hybridisation and large insert clone fluorescent in situ hybridisation. In two sibs and a fourth patient, cytogenetic and molecular-cytogenetic analyses showed the terminal deletions in 18p (8.0 and 13.84 Mb, respectively) to be accompanied by partial trisomies of 20p. Literature analyses of typical phenotypic features of 18pÀ, 8qþ and 20pþ syndromes allowed the attribution of clinical findings in our patients to the respective chromosomal aberration. Based on these data, we propose a phenotype map for several clinical features of the 18pÀ syndrome: Round face was tentatively mapped to the distal 1.6 Mb of 18p; post-natal growth retardation and seizures to the distal 8 Mb and ptosis and short neck to the proximal half of 18p.

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Section: Discussionmentioning

confidence: 99%

Towards mapping phenotypical traits in 18p− syndrome by array-based comparative genomic hybridisation and fluorescent in situ hybridisation

et al. 2006

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“…By releasing ubiquitin molecules from the substrate, USP14/Ubp6 helps to prevent the rapid degradation of ubiquitin molecules together with the substrate protein ( Hanna et al , 2007). A critical role of USP14 in stabilizing cellular ubiquitin levels was demonstrated in vivo in USP14 deficient ax J mice which display decreased ubiquitin levels in all tissues with the greatest loss observed at synaptic terminals ( Anderson et al , 2005; Wilson et al , 2002). …”

Section: Introductionmentioning

confidence: 99%

Does inactivation of USP14 enhance degradation of proteasomal substrates that are associated with neurodegenerative diseases?

2016

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A common pathological hallmark of age-related neurodegenerative diseases is the intracellular accumulation of protein aggregates such as α-synuclein in Parkinson’s disease, TDP-43 in ALS, and tau in Alzheimer’s disease. Enhancing intracellular clearance of aggregation-prone proteins is a plausible strategy for slowing progression of neurodegenerative diseases and there is great interest in identifying molecular targets that control protein turnover. One of the main routes for protein degradation is through the proteasome, a multisubunit protease that degrades proteins that have been tagged with a polyubiquitin chain by ubiquitin activating and conjugating enzymes. Published data from cellular models indicate that Ubiquitin-specific protease 14 (USP14), a deubiquitinating enzyme (DUB), slows the degradation of tau and TDP-43 by the proteasome and that an inhibitor of USP14 increases the degradation of these substrates. We conducted similar experiments designed to evaluate tau, TDP-43, or α-synuclein levels in cells after overexpressing USP14 or knocking down endogenous expression by siRNA.

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“…Dysfunction of the ubiquitination and deubiquitination machineries, mutations in ubiquitin, proteasomal impairment, and mutations in proteasome substrates affecting their rate of degradation underlie the pathogenesis of many neurodegenerative diseases (Dennissen et al, 2012). For instance, the ataxic mouse (ax J ), which results from a mutation in the ataxia gene encoding for the DUB Usp14, shows deficits in presynaptic neurotransmitter release and short-term plasticity (Wilson et al, 2002), in addition to a 35% decrease in free ubiquitin levels when compared to wildtype mice . Usp14 overexpression rescued the levels of free ubiquitin in the brain, as well as the lifespan and motor activity of ax J mice to values similar to the wildtype (Crimmins et al, 2006).…”

Section: Role Of Ups In Nervous Systemmentioning

confidence: 99%

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

117

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A B S T R A C TThe ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitincontaining proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. ß

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Synaptic defects in ataxia mice result from a mutation in Usp14, encoding a ubiquitin-specific protease

Cited by 246 publications

References 27 publications

Towards mapping phenotypical traits in 18p− syndrome by array-based comparative genomic hybridisation and fluorescent in situ hybridisation

Towards mapping phenotypical traits in 18p− syndrome by array-based comparative genomic hybridisation and fluorescent in situ hybridisation

Does inactivation of USP14 enhance degradation of proteasomal substrates that are associated with neurodegenerative diseases?

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

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