Progressive degeneration of motor nerve terminals in GAD mutant mouse with hereditary sensory axonopathy

Miura, Hiroyuki; Oda, Kenichiro; Endo, Chiyoko; Yamazaki, Kazuto; Shibasaki, Hiroshi; Kikuchi, Tateki

doi:10.1111/j.1365-2990.1993.tb00403.x

Cited by 44 publications

(31 citation statements)

References 18 publications

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“…This accompanied paralysis and premature death, probably as a result of respiratory failure caused by neuromuscular dysfunction and degeneration. These results are consistent with those of previous studies in the spontaneous mutation of UCH-L1 in gad mutant mice (16,17). However, those studies of gad mutants do not indicate the extent to which NMJ transmission is affected.…”

Section: Discussionsupporting

confidence: 83%

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Ubiquitin carboxyl-terminal hydrolase L1 is required for maintaining the structure and function of the neuromuscular junction

Chen

Sugiura

Myers

et al. 2010

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

119

107

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The enzyme ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is one of the most abundant proteins in the mammalian nervous system. In humans, UCH-L1 is also found in the ubiquitinated inclusion bodies that characterize neurodegenerative diseases in the brain, suggesting its involvement in neurodegeneration. The physiologic role of UCH-L1 in neurons, however, remains to be further elucidated. For example, previous studies have provided evidence both for and against the role of UCH-L1 in synaptic function in the brain. Here, we have characterized a line of knockout mice deficient in the UCH-L1 gene. We found that, in the absence of UCH-L1, synaptic transmission at the neuromuscular junctions (NMJs) is markedly impaired. Both spontaneous and evoked synaptic activity are reduced; paired pulse-facilitation is impaired, and synaptic transmission fails to respond to high-frequency, repetitive stimulation at the NMJs of UCH-L1 knockout mice. Morphologic analyses of the NMJs further revealed profound structural defects-loss of synaptic vesicles and accumulation of tubulovesicular structures at the presynaptic nerve terminals, and denervation of the muscles in UCH-L1 knockout mice. These findings demonstrate that UCH-L1 is required for the maintenance of the structure and function of the NMJ and that the loss of normal UCH-L1 activity may result in neurodegeneration in the peripheral nervous system. electrophysiology | knockout mice | neurodegeneration | synaptic transmission

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Section: Discussionsupporting

confidence: 83%

“…In fact, both sensory and motor nerves degenerate in gad mice (16,17), but the mechanisms underlying the nerve degeneration in these mutant mice remain poorly understood. This lack of understanding is due, in part, to the lack of understanding of the physiologic role of UCH-L1 in neuron.…”

mentioning

confidence: 99%

Ubiquitin carboxyl-terminal hydrolase L1 is required for maintaining the structure and function of the neuromuscular junction

Chen

Sugiura

Myers

et al. 2010

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

119

107

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“…Deletion of exons 7 and 8 of UCHL-1 in mice suffering from gracile axonal dystrophy is characterized by accumulation of ubiquitin-positive protein deposits in affected sensory and motor neurons (Saigoh et al, 1999). Yet UCHL-1 transgenic mice do not develop a parkinsonian phenotype (Mukoyama et al, 1989;Miura et al, 1993;Oda et al, 1992;Saigoh et al, 1999;Kurihara et al, 2001). Together, these observations show abnormal protein degradation and neuronal degeneration as a result of irregular UCHL-1 protein targeting, although resulting divergent phenotypes probably depend on a combination of several conditioning factors.…”

Section: Discussionmentioning

confidence: 99%

Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies

Barrachina

Castaño

Dalfó

et al. 2006

Neurobiology of Disease

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Parkinson disease (PD) and dementia with Lewy bodies (DLB) are characterized by the accumulation of abnormal a-synuclein and ubiquitin in protein aggregates conforming Lewy bodies and Lewy neurites. Ubiquitin C-terminal hydrolase-1 (UCHL-1) disassembles polyubiquitin chains to increase the availability of free monomeric ubiquitin to the ubiquitin proteasome system (UPS) thus favoring protein degradation. Since mutations in the UCHL-1 gene, reducing UPS activity by 50%, have been reported in autosomal dominant PD, and UCHL-1 inhibition results in the formation of a-synuclein aggregates in mesencephalic cultured neurons, the present study was initiated to test UCHL-1 mRNA and protein levels in post-mortem frontal cortex (area 8) of PD and DLB cases, compared with agematched controls. TaqMan PCR assays, and Western blots demonstrated down-regulation of UCHL-1 mRNA and UCHL-1 protein in the cerebral cortex in DLB (either in pure forms, not associated with Alzheimer disease: AD, and in common forms, with accompanying AD changes), but not in PD, when compared with age-matched controls. Interestingly, UCHL-1 mRNA and protein expressions were reduced in the medulla oblongata in the same PD cases. Moreover, UCHL-1 protein was decreased in the substantia nigra in cases with Lewy body pathology. UCHL-1 down-regulation was not associated with reduced protein levels of several proteasomal subunits, including 20SX, 20SY, 19S and 11Sa. Yet UCHL-3 expression was reduced in the cerebral cortex of PD and DLB patients. Together, these observations show reduced UCHL-1 expression as a contributory factor in the abnormal protein aggregation in DLB, and points UCHL-1 as a putative therapeutic target in the treatment of DLB. D

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“…A neuronal phenotype similar to that of Ufd2a ϩ/Ϫ mice was described for gad mice, which harbor an in-frame deletion in the Uchl1 gene (41); these animals thus exhibit gracile axonal dystrophy (GAD), characterized by the "dying-back" type of axonal degeneration and formation of spheroid bodies in nerve terminals (20,30,32,36). UCH-L1 is a member of the ubiquitin COOH-terminal hydrolysis (UCH) family of proteins, and its expression is restricted to the brain and testis (18,42).…”

Section: Discussionmentioning

confidence: 99%

Mammalian E4 Is Required for Cardiac Development and Maintenance of the Nervous System

Kaneko-Oshikawa

Nakagawa

Yamada

et al. 2005

Molecular and Cellular Biology

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Ubiquitin conjugation typically requires three classes of enzyme: E1, E2, and E3. A fourth type of enzyme (E4), however, was recently shown to be required for the degradation of certain types of substrate in yeast. We previously identified UFD2a (also known as E4B) as an E4 in mammals. UFD2a is exclusively expressed in cardiac muscle during mouse embryonic development, but it is abundant in neurons of adult mice and is implicated in the pathogenesis of neurodegenerative disease. The precise physiological function of this enzyme has remained largely unknown, however. Here, we show that mice lacking UFD2a die in utero, manifesting marked apoptosis in the developing heart. Polyubiquitylation activity for an E4 substrate was greatly reduced in Ufd2a ؊/؊ mouse embryonic fibroblasts. Furthermore, Ufd2a ؉/؊ mice displayed axonal dystrophy in the nucleus gracilis, as well as degeneration of Purkinje cells accompanied by endoplasmic reticulum stress. These animals also developed a neurological disorder. UFD2a thus appears to be essential for the development of cardiac muscle, as well as for the protection of spinocerebellar neurons from degeneration induced by endoplasmic reticulum stress.The ubiquitin (Ub)-proteasome system for protein degradation plays a pivotal role in many cellular processes (10, 38). The ubiquitylation of proteins serves to mark them for degradation by the proteasome, an ATP-dependent multiprotease complex. Protein ubiquitylation is achieved by a multistep mechanism involving several enzymes: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin-protein ligase (E3). A new class of ubiquitylation enzyme, a ubiquitin chain assembly factor (E4), was recently discovered and shown to be required for the degradation of certain types of substrate, including a fusion protein with an NH 2 -terminal ubiquitin moiety, by a ubiquitin fusion degradation pathway, designated UFD (17, 21). Ufd2 of Saccharomyces cerevisiae, the prototype E4 enzyme, binds to oligoubiquitylated UFD substrate and catalyzes extension of the ubiquitin chain. Lysine-29 of the ubiquitin moiety of the UFD substrate is required for polyubiquitylation by E4. A UFD substrate molecule with a short chain of Lys-29-linked ubiquitin molecules is thus presented by the Cdc48-Ufd1-Npl4 complex to Ufd2, which then mediates further elongation of the oligoubiquitin chain in a manner dependent on Lys-48 of ubiquitin. The polyubiquitylated UFD substrate is recognized by the UBL-UBA proteins Rad23 and Dsk2 and is then degraded by the 26S proteasome (40). In yeast, Ufd2 is implicated in proteolysis by the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway.Ufd2 and its homologs in other eukaryotes share a conserved domain known as the U box. The U box of Ufd2 mediates the interaction of this protein with ubiquitin-conjugated targets and therefore appears to be an essential functional domain for E4 activity. We recently showed that mammalian U-box proteins, including UFD2a (also known as E4B), also possess E3 a...

show abstract

Progressive degeneration of motor nerve terminals in GAD mutant mouse with hereditary sensory axonopathy

Cited by 44 publications

References 18 publications

Ubiquitin carboxyl-terminal hydrolase L1 is required for maintaining the structure and function of the neuromuscular junction

Ubiquitin carboxyl-terminal hydrolase L1 is required for maintaining the structure and function of the neuromuscular junction

Reduced ubiquitin C-terminal hydrolase-1 expression levels in dementia with Lewy bodies

Mammalian E4 Is Required for Cardiac Development and Maintenance of the Nervous System

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