Disease relevance of Usp14

• Undetectable levels of ataxia telangiectasia (ATM), which is required for proper development of the Purkinje dendritic arbor, were found in postnatal transgenic cerebella [1].
• Spinocerebellar ataxia type 1 (SCA1) is one of nine inherited, typically adult onset, polyglutamine neurodegenerative diseases [2].
• Episodic ataxia (EA) is a rare, familial disorder producing attacks of generalized ataxia, with normal or near-normal neurological function between attacks [3].
• At postnatal day 16-22 Aldh5a1-/- mice display ataxia and develop generalized seizures leading to rapid death [4].
• In adulthood, Ireb2(-/-) mice develop a movement disorder characterized by ataxia, bradykinesia and tremor [5].

Psychiatry related information on Usp14

• Angelman syndrome (AS) is a human genetic disorder characterized by mental retardation, seizures, inappropriate laughter, abnormal galt, tremor and ataxia [6].
• NPHP may be associated with Leber congenital amaurosis, tapeto-retinal degeneration, cerebellar ataxia, cone-shaped epiphyses, congenital oculomotor apraxia and hepatic fibrosis [7].
• The dominant polyglutamine expansion diseases, which include spinocerebellar ataxia type 1 (SCA1) and Huntington disease, are progressive, untreatable, neurodegenerative disorders [8].
• Motor incoordination (ataxia), a common characteristic of many neurological disorders, may reflect disordered balance, muscle strength, proprioception, and/or patterned gait [9].
• Gerstmann-Sträussler-Scheinker disease is an autosomal dominant disorder with a wide spectrum of clinical presentations including ataxia, spastic paraparesis, extrapyramidal signs, and dementia [10].

High impact information on Usp14

• We previously reported that a (CTG)n expansion causes spinocerebellar ataxia type 8 (SCA8), a slowly progressive ataxia with reduced penetrance [11].
• Mice homozygous with respect to the woozy (wz) mutation develop adult-onset ataxia with cerebellar Purkinje cell loss [12].
• In the mouse, homozygous mutations in Reln result in the reeler phenotype, characterized by ataxia and disrupted cortical layers [13].
• Mutations in a novel gene encoding a CRAL-TRIO domain cause human Cayman ataxia and ataxia/dystonia in the jittery mouse [14].
• Cayman ataxia is a recessive congenital ataxia restricted to one area of Grand Cayman Island. Comparative mapping suggested that the locus on 19p13.3 associated with Cayman ataxia might be homologous to the locus on mouse chromosome 10 associated with the recessive ataxic mouse mutant jittery [14].

Chemical compound and disease context of Usp14

• Spectrin mutations are a previously unknown cause of ataxia and neurodegenerative disease that affect membrane proteins involved in glutamate signaling [15].
• Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation [16].
• Multiple system atrophy (MSA) is a fatal neurodegenerative disorder presenting with autonomic failure and motor impairment, primarily comprising L-dopa-resistant parkinsonism but occasionally involving cerebellar ataxia [17].
• These results indicate that the increase in mitochondrial reactive oxygen species can result in biochemical aberrations with features reminiscent of mitochondrial myopathy, Friedreich ataxia, and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency [18].
• Ataxia telangiectasia (A-T) is an autosomal recessive disease caused by loss of function of the serine/threonine protein kinase ATM (ataxia telangiectasia mutated) [19].

Biological context of Usp14

• Cloning and chromosomal localization of mouse aquaporin 4: exclusion of a candidate mutant phenotype, ataxia [20].
• The function of the closely linked ataxia locus is not disrupted by the transgene insertion [21].
• The transgene-induced mutation 9257 and the spontaneous mutation twirler cause craniofacial and inner ear malformations and are located on mouse chromosome 18 near the ataxia locus ax [22].
• The results demonstrate that ataxia and the insertional mutation TgN9257Mm are separated by less than 1 cM and are located approximately 3 cM from the centromere, while the balding locus is 7 cM more distal [23].
• Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1 [3].

Anatomical context of Usp14

• Although pathological defects appear to be limited to the central nervous system, reduction of Usp14 expression was widespread in the ax(J) mice [24].
• Mice that are homozygous with respect to a mutation (ax(J)) in the ataxia (ax) gene develop severe tremors by 2-3 weeks of age followed by hindlimb paralysis and death by 6-10 weeks of age [25].
• Transgenic mice carrying the spinocerebellar ataxia type 1 (SCA1) gene, a polyglutamine neurodegenerative disorder, develop ataxia with ataxin-1 localized to aggregates within cerebellar Purkinje cells nuclei [26].
• Sensory ataxia and muscle spindle agenesis in mice lacking the transcription factor Egr3 [27].
• Nevertheless, these mice exhibit severe generalized tremoring and mild ataxia, and electrophysiological analysis showed conduction deficits consistent with reduced insulative capacity of the myelin sheath [28].

Associations of Usp14 with chemical compounds

• Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor [29].
• Mutations in another protein containing a CRAL-TRIO domain, alpha-tocopherol transfer protein (TTPA), cause a vitamin E-responsive ataxia [14].
• RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia [8].
• Thus, a purely electrical alteration is sufficient to cause cerebellar ataxia, and SK openers such as the neuroprotective agent riluzole may reduce neuronal hyperexcitability and have therapeutic value [30].
• In vivo sensitivity of the individual mice was evaluated by measuring brain ethanol levels at a precise behavioral end point, recovery from ataxia [31].

Physical interactions of Usp14

• Nova is a neuron-specific RNA binding protein targeted in patients with the autoimmune disorder paraneoplastic opsoclonus-myoclonus ataxia, which is characterized by failure of inhibition of brainstem and spinal motor systems [32].
• Ataxia and paroxysmal dyskinesia in mice lacking axonally transported FGF14 [33].
• These data indicate that the decrease of second messenger linked PKC activity and InsP3 receptor binding in CB may be a biochemical marker that reflects neuronal degeneration in dominant cerebellar ataxia [34].

Regulatory relationships of Usp14

• Grafted cerebellar cells in a mouse model of hereditary ataxia express IGF-I system genes and partially restore behavioral function [35].
• Surprisingly, mice in which the Atm gene has been inactivated lack distinct behavioral ataxia or pronounced cerebellar degeneration, the hallmarks of the human disease [36].
• Like DNA damaging agents, single-stranded DNA up-regulated p53 and activated the nuclear kinase ataxia telangiectasia mutant (ATM) as evidenced by phosphorylation of histone 2AX, an endogenous ATM substrate [37].
• Cerebellar granule-cell-specific GABAA receptors attenuate benzodiazepine-induced ataxia: evidence from alpha 6-subunit-deficient mice [38].
• Targeted disruption of the murine Nhe1 locus induces ataxia, growth retardation, and seizures [39].

Other interactions of Usp14

• Synaptic defects in ataxia mice result from a mutation in Usp14, encoding a ubiquitin-specific protease [25].
• During breeding of the TTR-HNF-3beta transgenic mice we noticed that they displayed severe ataxia [1].
• Fgf14-deficient mice were viable, fertile, and anatomically normal, but developed ataxia and a paroxysmal hyperkinetic movement disorder [33].
• The Cacng2 gene is disrupted in the stargazer mouse, with its distinctive phenotype including ataxia, frequent absence seizure episodes, and head elevation [40].
• Af4 is mutated in the robotic mouse that is characterized by ataxia and Purkinje cell loss [41].

Analytical, diagnostic and therapeutic context of Usp14

• A murine model of ataxia telangiectasia was created by disrupting the Atm locus via gene targeting [42].
• We have applied spectral karyotyping (SKY) to chemically induced plasmocytomas, mammary gland tumours from transgenic mice overexpressing the c-myc oncogene and thymomas from mice deficient for the ataxia telangiectasia (Atm) gene [43].
• Grafting experiments carried out on the cerebellum of the adult pcd (Purkinje-cell-degeneration) mutant mouse (an animal model of hereditary degenerative ataxia) reveal that embryonic Purkinje cells, by some unknown sorting mechanism, selectively invade the deprived cerebellar cortex [44].
• Neuronal degeneration and Lafora inclusion bodies predate the onset of impaired behavioral responses, ataxia, spontaneous myoclonic seizures and EEG epileptiform activity [45].
• These transgenic mice developed progressive neurological phenotypes of muscular weakness and ataxia, small body size and short life-span [46].

References