Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The gracile axonal dystrophy (gad) mouse is an autosomal recessive mutant that shows sensory ataxia at an early stage, followed by motor ataxia at a later stage. Pathologically, the mutant is characterized by 'dying-back' type axonal degeneration and formation of spheroid bodies in nerve terminals. Recent pathological observations have associated brain ageing and neurodegenerative diseases with progressive accumulation of ubiquitinated protein conjugates. In gad mice, accumulation of amyloid beta-protein and ubiquitin-positive deposits occur retrogradely along the sensory and motor nervous systems. We previously reported that the gad mutation was transmitted by a gene on chromosome 5 (refs 10,11). Here we find that the gad mutation is caused by an in-frame deletion including exons 7 and 8 of Uchl1, encoding the ubiquitin carboxy-terminal hydrolase (UCH) isozyme (Uch-l1) selectively expressed in the nervous system and testis. The gad allele encodes a truncated Uch-l1 lacking a segment of 42 amino acids containing a catalytic residue. As Uch-l1 is thought to stimulate protein degradation by generating free monomeric ubiquitin, the gad mutation appears to affect protein turnover. Our data suggest that altered function of the ubiquitin system directly causes neurodegeneration. The gad mouse provides a useful model for investigating human neurodegenerative disorders.
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PMID:Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice. 1047 87

Altered function of the ubiquitin pathway has been implicated in the etiology of neurodegeneration. For example, gracile axonal dystrophy (gad) mutant mice, which harbor a deletion within the gene encoding ubiquitin C-terminal hydrolase L1 (Uch-L1), display sensory ataxia followed by posterior paralysis and lethality. We previously showed that mice homozygous for a targeted deletion of the related Uch-L3 gene are indistinguishable from wild-type. To assess whether the two hydrolases have redundant function, we generated mice homozygous for both Uch-L1gad and Uch-L3Delta3-7. The double homozygotes weigh 30% less than single homozygotes and display an earlier onset of lethality, possibly due to dysphagia, a progressive loss in the ability to swallow food. This is consistent with histological analysis that revealed axonal degeneration of the nucleus tractus solitarius (NTS) and area postrema (AP) of the medulla. The NTS is essential for central nervous system control of swallowing. The double homozygotes also display a more severe axonal degeneration of the gracile tract of the medulla and spinal cord than had been observed in Uch-L1gad single homozygotes. In addition, degeneration of dorsal root ganglia cell bodies was detected in both the double homozygotes and Uch-L3Delta3-7 single homozygotes. Given that both Uch-L1gad and Uch-L3Delta3-7 single homozygotes display distinct degenerative defects that are exacerbated in the double homozygotes, we conclude that Uch-L1 and Uch-L3 have both separate and overlapping functions in the maintenance of neurons of the gracile tract, NTS and AP. This study is the first to successfully document dysphagia in the mouse and is a potentially valuable resource for understanding human neurodegenerative disorders that cause swallowing defects.
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PMID:Loss of Uch-L1 and Uch-L3 leads to neurodegeneration, posterior paralysis and dysphagia. 1155 33

The gracile axonal dystrophy (gad) mutation in Uch-l1, the gene encoding the ubiquitin carboxy-terminal hydrolase isozyme L1 (UCH-L1), causes selective dying back degeneration of dorsal root ganglion neuron in the medulla oblongata along with progressive sensory-motor ataxia. Axonal spheroids are observed within degenerating axons, and their contents may illuminate the pathogenic mechanisms leading to neurodegeneration in gad mice. To analyze changes in negatively charged lipid molecules in dystrophic axons of gad mice, we performed matrix-assisted laser desorption/ionization (MALDI)-imaging mass spectrometry (IMS), electron microscopy, and fluorescence immunohistochemistry on tissue sections from gad and wild-type mouse medulla. MALDI-IMS revealed that m/z 806.68 and 822.68 molecules, assigned to sulfatide (ST) C18:0 and ST C18:0(OH), respectively, were concentrated in the dorsomedial medulla. This spatial distribution overlapped significantly with that of axonal spheroids. Immunostaining revealed that spheroids accumulated myelin and lymphocyte protein, a known ST binding protein. Sulfatides with short-chain fatty acids (C16-C20) are generally localized in intracellular vesicles; therefore, ST C18:0 accumulation may reflect intracellular vesicle aggregation within spheroids. Ubiquitin system disruption apparently alters lipid metabolism, membrane organization, protein turnover, and axonal transport. Changes in membrane organization, particularly STs within lipid rafts, may disrupt cellular signaling pathways necessary for neuronal viability.
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PMID:Sulfatide accumulation in the dystrophic terminals of gracile axonal dystrophy mice: lipid analysis using matrix-assisted laser desorption/ionization imaging mass spectrometry. 2341 24

Background: Friedreich's ataxia (FRDA) is the most common autosomal recessive ataxia. Disease-modifying treatments are not available yet; however, several compounds are currently under investigation. As a result, there is a growing need for the identification of robust and easily accessible biomarkers for the monitoring of disease activity and therapeutic efficacy. The simultaneous measurement of multiple brain-derived proteins could represent a time- and cost-efficient approach for biomarker investigation in pathologically complex neurodegenerative diseases like FRDA. Objectives: To investigate the role of plasma neurofilament-light chain (NfL), glial fibrillary acidic protein (GFAP), total tau (t-tau) and ubiquitin C-terminal hydrolase L1(UCHL1) as biomarkers in FRDA. Additionally, NfL measurements derived from the novel multiplex assay were compared to those from an established NfL singleplex assay. Methods: In this study, an ultrasensitive Single molecule array (Simoa) 4-plex assay was used for the measurement of plasma NfL, GFAP, t-tau, and UCHL1 in 33 FRDA patients and 13 age-matched controls. Differences in biomarker concentrations between these groups were computed and associations with genetic and disease related parameters investigated. Additionally, the agreement between NfL measurements derived from the 4-Plex and an established Simoa NfL singleplex assay was assessed. Results: Mean plasma NfL, GFAP and UCHL1 levels were significantly higher in FRDA patients than in controls (NfL: p < 0.001; GFAP: p = 0.006, and UCHL1: p = 0.020). Conversely, there was no significant difference in concentrations of t-tau in the patient and control group (p = 0.236). None of the proteins correlated with the GAA repeat length or the employed measures of disease severity. The individual NfL values derived from the two assays showed a strong concordance (rc = 0.93). Although the mean difference of 1.29 pg/mL differed significantly from 0 (p = 0.006), regression analysis did not indicate the presence of a proportional bias. Conclusion: This is the first study demonstrating that NfL, GFAP, and UCHL1 levels are raised in FRDA, potentially reflecting ongoing neuronal degeneration and glial activation. Further studies are required to determine their role as marker for disease activity and progression. Furthermore, the novel 4-plex assay appears to be a valid tool to simultaneously measure brain-derived proteins at extremely low concentrations in the peripheral circulation.
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PMID:Plasma Markers of Neurodegeneration Are Raised in Friedreich's Ataxia. 3042 21