Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0851184 (thinning)
 11,252 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spinocerebellar ataxia type 7 (SCA7) is a dominantly inherited disorder characterized by cerebellum and brainstem neurodegeneration. SCA7 is caused by a CAG/polyglutamine (polyQ) repeat expansion in the ataxin-7 gene. We previously reported that directed expression of polyQ-ataxin-7 in Bergmann glia (BG) in transgenic mice leads to ataxia and non-cell-autonomous Purkinje cell (PC) degeneration. To further define the cellular basis of SCA7, we derived a conditional inactivation mouse model by inserting a loxP-flanked ataxin-7 cDNA with 92 repeats into the translational start site of the murine prion protein (PrP) gene in a bacterial artificial chromosome (BAC). The PrP-floxed-SCA7-92Q BAC mice developed neurological disease, and exhibited cerebellar degeneration and BG process loss. To inactivate polyQ-ataxin-7 expression in specific cerebellar cell types, we crossed PrP-floxed-SCA7-92Q BAC mice with Gfa2-Cre transgenic mice (to direct Cre to BG) or Pcp2-Cre transgenic mice (which yields Cre in PCs and inferior olive). Excision of ataxin-7 from BG partially rescued the behavioral phenotype, but did not prevent BG process loss or molecular layer thinning, while excision of ataxin-7 from PCs and inferior olive provided significantly greater rescue and prevented both pathological changes, revealing a non-cell-autonomous basis for BG pathology. When we prevented expression of mutant ataxin-7 in BG, PCs, and inferior olive by deriving Gfa2-Cre;Pcp2-Cre;PrP-floxed-SCA7-92Q BAC triple transgenic mice, we noted a dramatic improvement in SCA7 disease phenotypes. These findings indicate that SCA7 disease pathogenesis involves a convergence of alterations in a variety of different cell types to fully recapitulate the cerebellar degeneration.
 ...
PMID:Spinocerebellar ataxia type 7 cerebellar disease requires the coordinated action of mutant ataxin-7 in neurons and glia, and displays non-cell-autonomous bergmann glia degeneration. 2207 78

Spinocerebellar ataxia type 7 (SCA7) is a late-onset neurodegenerative disease characterized by ataxia and vision loss with no effective treatments in the clinic. The most striking feature is the degeneration of Purkinje neurons of the cerebellum caused by the presence of polyglutamine-expanded ataxin-7. Ataxin-7 is part of a transcriptional complex, and, in the setting of mutant ataxin-7, there is misregulation of target genes. Here, we designed RNAi sequences to reduce the expression of both wildtype and mutant ataxin-7 to test if reducing ataxin-7 in Purkinje cells is both tolerated and beneficial in an animal model of SCA7. We observed sustained reduction of both wildtype and mutant ataxin-7 as well as a significant improvement of ataxia phenotypes. Furthermore, we observed a reduction in cerebellar molecular layer thinning and nuclear inclusions, a hallmark of SCA7. In addition, we observed recovery of cerebellar transcripts whose expression is disrupted in the presence of mutant ataxin-7. These data demonstrate that reduction of both wildtype and mutant ataxin-7 by RNAi is well tolerated, and contrary to what may be expected from reducing a component of the Spt-Taf9-Gcn5 acetyltransferase complex, is efficacious in the SCA7 mouse.
...
PMID:Nonallele specific silencing of ataxin-7 improves disease phenotypes in a mouse model of SCA7. 2493 Jun 1