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)

Spinocerebellar ataxia (SCA) in the Parson Russell Terrier (PRT) dog breed is a disease of progressive incoordination of gait and loss of balance. Clinical signs usually become notable between 6 and 12 months of age with affected dogs presenting with symmetric spinocerebellar ataxia particularly evident in the pelvic limbs. The degree of truncal ataxia, pelvic limb hypermetria and impaired balance is progressive, particularly during the initial months of disease. A certain degree of stabilisation as well as intermittent worsening may occur. At the later stages of the disease ambulation often becomes difficult, with owners often electing to euthanise affected dogs on welfare grounds. Using a GWAS approach and target-enriched massively-parallel sequencing, a strongly associated non-synonymous SNP in the CAPN1 gene, encoding the calcium dependent cysteine protease calpain1 (mu-calpain), was identified. The SNP is a missense mutation causing a cysteine to tyrosine substitution at residue 115 of the CAPN1 protein. Cysteine 115 is a highly conserved residue and forms a key part of a catalytic triad of amino acids that are crucial to the enzymatic activity of cysteine proteases. The CAPN1 gene shows high levels of expression in the brain and nervous system and roles for the protein in both neuronal necrosis and maintenance have been suggested. Given the functional implications and high level of conservation observed across species, the CAPN1 variant represents a provocative candidate for the cause of SCA in the PRT and a novel potential cause of ataxia in humans.
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PMID:Missense mutation in CAPN1 is associated with spinocerebellar ataxia in the Parson Russell Terrier dog breed. 2374 57

A CAPN1 missense mutation in Parson Russell Terrier dogs is associated with spinocerebellar ataxia. We now report that homozygous or heterozygous CAPN1-null mutations in humans result in cerebellar ataxia and limb spasticity in four independent pedigrees. Calpain-1 knockout (KO) mice also exhibit a mild form of ataxia due to abnormal cerebellar development, including enhanced neuronal apoptosis, decreased number of cerebellar granule cells, and altered synaptic transmission. Enhanced apoptosis is due to absence of calpain-1-mediated cleavage of PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), which results in inhibition of the Akt pro-survival pathway in developing granule cells. Injection of neonatal mice with the indirect Akt activator, bisperoxovanadium, or crossing calpain-1 KO mice with PHLPP1 KO mice prevented increased postnatal cerebellar granule cell apoptosis and restored granule cell density and motor coordination in adult mice. Thus, mutations in CAPN1 are an additional cause of ataxia in mammals, including humans.
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PMID:Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans. 2732 Sep 12

Calpain-1 deletion elicits neurodevelopmental disorders, such as ataxia. However, the function of calpain in postnatal neurodevelopment and its mechanisms remain unknown. In this study, we revealed that postnatal intraperitoneal injection of various calpain inhibitors attenuated cerebellar cytosolic calpain activity. Moreover, postnatal application of calpeptin (2 mg/kg) apparently reduced spectrin breakdown, promoted suprachiasmatic nucleus circadian oscillatory protein (SCOP) accumulation in cerebellar tissue. In addition, application of calpeptin decreased phosphorylated protein kinase B (p-AKT) level (p<0.05), as well as total AKT level (p<0.05). We also evidenced that administration of calpeptin obviously increased phosphorylation of mammalian target of rapamycin (p-mTor) (p<0.01). Apoptosis of granular cells and activation of caspase-3 (p<0.01) were facilitated after calpain inhibition. Importantly, cell numbers of granular cells were reduced and motor function was remarkably impaired in 4-month-old rats receiving postnatal calpain inhibition. Taken together, our data implicated that calpain activity in the postnatal period was critical for the cerebellar development. Postnatal calpain inhibition causes cerebellar granular cell apoptosis and motor dysfunction, likely through SCOP/AKT and p-mTor signaling pathways.
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PMID:Postnatal calpain inhibition elicits cerebellar cell death and motor dysfunction. 2915 36