Abstract |
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.
|
Authors | Stephanie A Furrer, Mathini S Mohanachandran, Sarah M Waldherr, Christopher Chang, Vincent A Damian, Bryce L Sopher, Gwenn A Garden, Albert R La Spada |
Journal | The Journal of neuroscience : the official journal of the Society for Neuroscience
(J Neurosci)
Vol. 31
Issue 45
Pg. 16269-78
(Nov 09 2011)
ISSN: 1529-2401 [Electronic] United States |
PMID | 22072678
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
|
Chemical References |
- ATXN7 protein, human
- Ataxin-7
- Atxn7 protein, mouse
- Nerve Tissue Proteins
- Peptides
- Prions
- RNA, Messenger
- polyglutamine
|
Topics |
- Analysis of Variance
- Animals
- Ataxin-7
- Disease Models, Animal
- Gene Expression Regulation
(genetics)
- Humans
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Motor Activity
(genetics)
- Mutation
(genetics)
- Nerve Tissue Proteins
(genetics, metabolism)
- Neuroglia
(pathology)
- Neurons
(pathology)
- Peptides
(genetics)
- Phenotype
- Prions
(genetics)
- RNA, Messenger
(metabolism)
- Rotarod Performance Test
- Spinocerebellar Ataxias
(genetics, pathology, physiopathology)
|