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Query: UMLS:C0004134 (
ataxia
)
15,886
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Spinocerebellar ataxia type 29 (SCA29) is autosomal dominant congenital
ataxia
characterized by early-onset motor delay, hypotonia, and gait
ataxia
. Recently, heterozygous missense mutations in an intracellular Ca
2+
channel, inositol 1,4,5-trisphosphate (IP
3
) receptor type 1 (IP
3
R1), were identified as a cause of SCA29. However, the functional impacts of these mutations remain largely unknown. Here, we determined the molecular mechanisms by which pathological mutations affect IP
3
R1 activity and Ca
2+
dynamics. Ca
2+
imaging using IP
3
R-null HeLa cells generated by genome editing revealed that all SCA29 mutations identified within or near the IP
3
-binding domain of IP
3
R1 completely abolished channel activity. Among these mutations, R241K, T267M, T267R, R269G, R269W, S277I, K279E, A280D, and E497K impaired IP
3
binding to IP
3
R1, whereas the T579I and N587D mutations disrupted channel activity without affecting IP
3
binding, suggesting that T579I and N587D compromise channel gating mechanisms. Carbonic anhydrase-related protein
VIII
(CA8) is an IP
3
R1-regulating protein abundantly expressed in cerebellar Purkinje cells and is a causative gene of congenital
ataxia
. The SCA29 mutation V1538M within the CA8-binding site of IP
3
R1 completely eliminated its interaction with CA8 and CA8-mediated IP
3
R1 inhibition. Furthermore, pathological mutations in CA8 decreased CA8-mediated suppression of IP
3
R1 by reducing protein stability and the interaction with IP
3
R1. These results demonstrated the mechanisms by which pathological mutations cause IP
3
R1 dysfunction, i.e., the disruption of IP
3
binding, IP
3
-mediated gating, and regulation via the IP
3
R-modulatory protein. The resulting aberrant Ca
2+
homeostasis may contribute to the pathogenesis of cerebellar ataxia.
...
PMID:Aberrant IP
3
receptor activities revealed by comprehensive analysis of pathological mutations causing spinocerebellar ataxia 29. 3042 31
Sporadic adult-onset
ataxia
of unknown etiology (SAOA) is a non-genetic neurodegenerative disorder of the cerebellum of unknown cause which manifests with progressive
ataxia
without severe autonomic failure. Although SAOA is associated with cerebellar degeneration, little is known about the specific cerebellar atrophy pattern in SAOA. Thirty-seven SAOA patients and 49 healthy controls (HCs) were included at two centers. We investigated the structural and functional characteristics of SAOA brains using voxel-based morphometry (VBM) and resting-state functional imaging (rs-fMRI). In order to examine the functional consequence of structural cerebellar alterations, the amplitude of low-frequency fluctuation (ALFF) and degree centrality (DC) were analyzed, and then assessed their relation with disease severity, disease duration, and age of onset within these regions. Group differences were investigated using two-sample t tests, controlling for age, gender, site, and the total intracranial volume. The VBM analysis revealed a significant, mostly bilateral reduction of local gray matter (GM) volume in lobules I-V, V, VI, IX, X, and vermis
VIII
a/b in SAOA patients, compared with HCs. The GM volume loss in these regions was significantly associated with disease severity, disease duration, and age of onset. The disease-related atrophy regions did not show any functional alternations compared with HCs but were functionally characterized by high ALFF and poor DC compared with intact cerebellar regions. Our data revealed volume reduction in SAOA in cerebellar regions that are known to be involved in motor and somatosensory processing, corresponding with the clinical phenotype of SAOA. Our data suggest that the atrophy occurs in those cerebellar regions which are characterized by high ALFF and poor DC. Further studies have to show if these findings are specific for SAOA, and if they can be used to predict disease progression.
...
PMID:Characterization of Cerebellar Atrophy and Resting State Functional Connectivity Patterns in Sporadic Adult-Onset Ataxia of Unknown Etiology (SAOA). 3142 50
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