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60 Impact of Reducing the Nuclear Mutant ATXN1 on Spinocerebellar Ataxia-Like Phenotype
- Kathleen B Mather, Lisa A Duvick, Hillary P Handler, Harry T Orr
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- Journal:
- Journal of the International Neuropsychological Society / Volume 29 / Issue s1 / November 2023
- Published online by Cambridge University Press:
- 21 December 2023, pp. 570-571
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Objective:
Spinocerebellar ataxia type one (SCA1) is an autosomal dominant neurodegenerative disease caused by an expanded CAG repeat that encodes glutamine (polyQ) in the affected ATXN1 gene. SCA1 pathology is commonly characterized by the degeneration of the cerebellar Purkinje cells (PC) and brainstem. Symptoms include motor dysfunction, cognitive impairments, bulbar dysfunction, and premature death. Atxn1175Q/2Q knock-in mice were previously developed to model SCA1 by inserting 175 expanded CAG repeats into one allele of the Atxn1 gene, producing mice expressing ATXN1 throughout the brain and displaying SCA1 symptoms. Previous research has indicated the role of localization of the ATXN1 protein to the nucleus in pathology. Therefore, the Atxn1175QK772T/2Q mouse model was created by disrupting the NLS in the expanded Atxn1175Q/2Q mice by replacing lysine with threonine at position 772 in the nuclear localization sequence (NLS). Since this amino acid change previously blocked PC disease in another mouse model, the Atxn1175QK772T/2Q mice were created to examine how the NLS mutation affects neuronal cells. RNA sequencing analysis was previously performed and found differentially expressed genes (DEG) with Atxn1175Q/2Q downregulated compared to Atxn1175QK772T/2Q and Atxn12Q/2Q in the cerebellum, medulla, cortex, hippocampus, and striatum. The aim was to analyze these brain regions to validate the RNAseq differential gene expression at a protein level.
Participants and Methods:Therefore, western blots were performed on the following mouse models (n=12): wild type mice (Atxn12Q/2Q), mice with the nuclear localization sequence mutation (Atxn12QK772T/2Q), and mice with 175 expanded CAG repeats (Atxn1175/2Q). Based off the RNAseq data, the cerebellum was tested with ion channel genes (Cav3.1, Kcnma1, and Trpc3) and the striatum was tested with a gene found in medium-spiny neurons (DARPP-32).
Results:In the cerebellum, Atxn1175/2Q was significantly downregulated compared to Atxn1175QK772T/2Q in Cav3.1, Trpc3, and Kcnma1. Atxn1175Q/2Q was significantly downregulated compared to Atxn12Q/2Q in Trpc3 and Kcnma1. Atxn1175QK772T/2Q was significantly downregulated compared to Atxn12Q/2Q in Trpc3. In the striatum, there was significantly reduced DARPP-32 expression found between Atxn12Q/2Q and Atxn1175QK772T/2Q, Atxn12Q/2Q and Atxn1175Q/2Q, and Atxn1175Q/2Q and Atxn1175QK772T/2Q.
Conclusions:Therefore, the significantly reduced gene expression at the protein level in the cerebellum and striatum validate RNAseq differentially expressed genes. Additionally, the downregulation of both the Atxn1175Q/2Q and Atxn1175QK772TQ/2Q compared to Atxn12Q/2Q in the striatum supports the lack of learning of those mouse models on the rotarod, suggesting that the nuclear localization mutation does not rescue learning. Interestingly, the downregulation of Atxn1175Q/2Q compared to Atxn1175QK772TQ/2Q likely supports the age-related motor decline rescue in the rotarod seen in Atxn1175QK772T/2Q and not Atxn1175Q/2Q.
Roles of instrumented farm-scale trials in trade-off assessments of pasture-based ruminant production systems
- T. Takahashi, P. Harris, M. S. A. Blackwell, L. M. Cardenas, A. L. Collins, J. A. J. Dungait, J. M. B. Hawkins, T. H. Misselbrook, G. A. McAuliffe, J. N. McFadzean, P. J. Murray, R. J. Orr, M. J. Rivero, L. Wu, M. R. F. Lee
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For livestock production systems to play a positive role in global food security, the balance between their benefits and disbenefits to society must be appropriately managed. Based on the evidence provided by field-scale randomised controlled trials around the world, this debate has traditionally centred on the concept of economic-environmental trade-offs, of which existence is theoretically assured when resource allocation is perfect on the farm. Recent research conducted on commercial farms indicates, however, that the economic-environmental nexus is not nearly as straightforward in the real world, with environmental performances of enterprises often positively correlated with their economic profitability. Using high-resolution primary data from the North Wyke Farm Platform, an intensively instrumented farm-scale ruminant research facility located in southwest United Kingdom, this paper proposes a novel, information-driven approach to carry out comprehensive assessments of economic-environmental trade-offs inherent within pasture-based cattle and sheep production systems. The results of a data-mining exercise suggest that a potentially systematic interaction exists between ‘soil health’, ecological surroundings and livestock grazing, whereby a higher level of soil organic carbon (SOC) stock is associated with a better animal performance and less nutrient losses into watercourses, and a higher stocking density with greater botanical diversity and elevated SOC. We contend that a combination of farming system-wide trials and environmental instrumentation provides an ideal setting for enrolling scientifically sound and biologically informative metrics for agricultural sustainability, through which agricultural producers could obtain guidance to manage soils, water, pasture and livestock in an economically and environmentally acceptable manner. Priority areas for future farm-scale research to ensure long-term sustainability are also discussed.
26 - Spinocerebellar ataxia type 1
- from PART VIII - DOMINANTLY INHERITED PROGRESSIVE ATAXIAS
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- By Xi Lin, Departments of Pediatrics, Neurology, Neuroscience, and Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College ofMedicine, Houston, Texas, USA, Harry T. Orr, Institute of Human Genetics, University of Minnesota, Minneapolis, USA, Huda Y. Zoghbi, Departments of Pediatrics, Neurology, Neuroscience, and Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, USA
- Edited by Mario-Ubaldo Manto, University of Brussels, Massimo Pandolfo, Université de Montréal
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- Book:
- The Cerebellum and its Disorders
- Published online:
- 06 July 2010
- Print publication:
- 15 November 2001, pp 409-418
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Summary
Introduction
Spinocerebellar ataxia type 1 (SCA1) is one of a complex group of autosomal dominant ataxias, which were first recognized as distinct from the recessive Friedreich's ataxia in 1893 by Marie. The clinicopathological presentations of these ataxias are extremely heterogeneous, with variable degrees of neurodegeneration in the cerebellum, spinal tracts, and brainstem. Thus, the classification of SCAs remained difficult and controversial until the 1990s, when the identification of distinct genes for several dominant ataxias allowed unequivocal genetic, if not clinical, differentiation (Orr and Zoghbi, 1996). SCA1 was one of the first neurogenetic diseases to be mapped to an autosome using classical linkage studies (Yakura et al., 1974; Jackson et al., 1977). The cloning of the SCA1 gene, the elucidation of a dynamic CAG trinucleotide repeat expansion as the mutational mechanism, and the establishment of cellular and animal models for this disorder have greatly advanced our understanding of the molecular and cellular mechanisms underlying SCA1 pathogenesis. These studies will undoubtedly provide the basis for developing effective therapeutics.
Clinical features
SCA1 usually strikes during the third or fourth decade of life, typically progressing over 10 to 15 years. In SCA1 families, the affected individuals in successive generations tend to have an earlier onset and more severe manifestations of the disease, a phenomenom referred to as anticipitation. Early onset in the first decade has been documented in such families (Schut, 1950; Zoghbi et al., 1988). The most salient clinical features of SCA1 include ataxia, dysarthria, and bulbar palsies. Other neurological abnormalities, such as extrapyramidal signs and peripheral neuropathy, often show extensive interfamilial and intrafamilial variability (Subramony and Vig, 1998; Zoghbi and Orr, 2000).