Dataset Information

Regional rescue of spinocerebellar ataxia type 1 phenotypes by 14-3-3epsilon haploinsufficiency in mice underscores complex pathogenicity in neurodegeneration.

ABSTRACT: Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a CAG repeat encoding a polyglutamine tract in Ataxin-1 (ATXN1). Both WT and mutant ATXN1 interact with 14-3-3 proteins, and 14-3-3 overexpression stabilizes ATXN1 levels in cells and increases ATXN1 toxicity in flies. To determine whether reducing 14-3-3 levels might mitigate SCA1 pathogenesis, we bred Sca1(154Q/+) mice to mice lacking one allele of 14-3-3?. 14-3-3? haploinsufficiency rescued cerebellar pathology and motor phenotypes but, surprisingly, not weight loss, respiratory dysfunction, or premature lethality. Biochemical studies revealed that reducing 14-3-3? levels exerted different effects in two brain regions especially vulnerable in SCA1: Although diminishing levels of both WT and mutant ATXN1 in the cerebellum, 14-3-3? haploinsufficiency did not alter ATXN1 levels in the brainstem. Furthermore, 14-3-3? haploinsufficiency decreased the incorporation of expanded ATXN1 into its large toxic complexes in the cerebellum but not in the brainstem, and the distribution of ATXN1's small and large native complexes differed significantly between the two regions. These data suggest that distinct pathogenic mechanisms operate in different vulnerable brain regions, adding another level of complexity to SCA1 pathogenesis.

SUBMITTER: Jafar-Nejad P

PROVIDER: S-EPMC3033247 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Regional rescue of spinocerebellar ataxia type 1 phenotypes by 14-3-3epsilon haploinsufficiency in mice underscores complex pathogenicity in neurodegeneration.

Jafar-Nejad Paymaan P Ward Christopher S CS Richman Ronald R Orr Harry T HT Zoghbi Huda Y HY

Proceedings of the National Academy of Sciences of the United States of America 20110118 5

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a CAG repeat encoding a polyglutamine tract in Ataxin-1 (ATXN1). Both WT and mutant ATXN1 interact with 14-3-3 proteins, and 14-3-3 overexpression stabilizes ATXN1 levels in cells and increases ATXN1 toxicity in flies. To determine whether reducing 14-3-3 levels might mitigate SCA1 pathogenesis, we bred Sca1(154Q/+) mice to mice lacking one allele of 14-3-3ε. 14-3-3ε haploinsufficiency rescued cerebell ...[more]

PMID: 21245341

Similar Datasets

Project description:Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited, neurodegenerative disease caused by an expansion of polyglutamine tracts in the cytosolic protein ataxin-2 (Atx2). Cerebellar Purkinje cells (PCs) are predominantly affected in SCA2. The cause of PC degeneration in SCA2 is unknown. Here we demonstrate that mutant Atx2-58Q, but not wild-type (WT) Atx2-22Q, specifically associates with the cytosolic C-terminal region of type 1 inositol 1,4,5-trisphosphate receptor (InsP(3)R1), an intracellular calcium (Ca(2+)) release channel. Association with Atx2-58Q increased the sensitivity of InsP(3)R1 to activation by InsP(3) in planar lipid bilayer reconstitution experiments. To validate physiological significance of these findings, we performed a series of experiments with an SCA2-58Q transgenic mouse model that expresses human full-length Atx2-58Q protein under the control of a PC-specific promoter. In Ca(2+) imaging experiments, we demonstrated that stimulation with 3,5-dihydroxyphenylglycine (DHPG) resulted in higher Ca(2+) responses in 58Q PC cultures than in WT PC cultures. DHPG-induced Ca(2+) responses in 58Q PC cultures were blocked by the addition of ryanodine, an inhibitor of the ryanodine receptor (RyanR). We further demonstrated that application of glutamate induced more pronounced cell death in 58Q PC cultures than in WT PC cultures. Glutamate-induced cell death of 58Q PC cultures was attenuated by dantrolene, a clinically relevant RyanR inhibitor and Ca(2+) stabilizer. In whole animal experiments, we demonstrated that long-term feeding of SCA1-58Q mice with dantrolene alleviated age-dependent motor deficits (quantified in beam-walk and rotarod assays) and reduced PC loss observed in untreated SCA2-58Q mice by 12 months of age (quantified by stereology). Results of our studies indicate that disturbed neuronal Ca(2+) signaling may play an important role in SCA2 pathology and also suggest that the RyanR constitutes a potential therapeutic target for treatment of SCA2 patients.

Project description:Spinocerebellar Ataxia type 7 (SCA7) is a neurodegenerative disease characterized by progressive cerebellar ataxia and retinal degeneration. Increasing loss of visual function complicates the use of clinical scales to track the progression of motor symptoms, hampering our ability to develop accurate biomarkers of disease progression, and thus test the efficacy of potential treatments. We aimed to identify imaging measures of neurodegeneration, which may more accurately reflect SCA7 severity and progression. While common structural MRI techniques have been previously used for this purpose, they can be biased by neurodegeneration-driven increases in extracellular CSF-like water. In a cross-sectional study, we analyzed diffusion tensor imaging (DTI) data collected from a cohort of 13 SCA7 patients and 14 healthy volunteers using: 1) a diffusion tensor-based image registration technique, and 2) a dual-compartment DTI model to control for the potential increase in extracellular CSF-like water. These methodologies allowed us to assess both volumetric and microstructural abnormalities in both white and gray matter brain-wide in SCA7 patients for the first time. To measure tissue volume, we performed diffusion tensor-based morphometry (DTBM) using the tensor-based registration. To assess tissue microstructure, we computed the parenchymal mean diffusivity (pMD) and parenchymal fractional anisotropy (pFA) using the dual compartment model. This model also enabled us to estimate the parenchymal volume fraction (pVF), a measure of parenchymal tissue volume within a given voxel. While DTBM and pVF revealed tissue loss primarily in the brainstem, cerebellum, thalamus, and major motor white matter tracts in patients (p < 0.05, FWE corrected; Hedge's g > 1), pMD and pFA detected microstructural abnormalities in virtually all tissues brain-wide (p < 0.05, FWE corrected; Hedge's g > 1). The Scale for the Assessment and Rating of Ataxia trended towards correlation with cerebellar pVF (r = -0.66, p = 0.104, FDR corrected) and global white matter pFA (r = -0.64, p = 0.104, FDR corrected). These results advance our understanding of neurodegeneration in living SCA7 patients by providing the first voxel-wise characterization of white matter volume loss and gray matter microstructural abnormalities. Moving forward, this comprehensive approach could be applied to characterize the full spatiotemporal pattern of neurodegeneration in SCA7, and potentially develop an accurate imaging biomarker of disease progression.

Dataset Information

Regional rescue of spinocerebellar ataxia type 1 phenotypes by 14-3-3epsilon haploinsufficiency in mice underscores complex pathogenicity in neurodegeneration.

Publications

Regional rescue of spinocerebellar ataxia type 1 phenotypes by 14-3-3epsilon haploinsufficiency in mice underscores complex pathogenicity in neurodegeneration.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets