Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine tract in ataxin-1 (ATXN1). SCA1 pathogenesis studies support a model in which the expanded glutamine tract causes toxicity by modulating the normal activities of ATXN1. To explore native interactions that modify the toxicity of ATXN1, we generated a targeted duplication of the mouse ataxin-1-like (Atxn1l, also known as Boat) locus, a highly conserved paralog of SCA1, and tested the role of this protein in SCA1 pathology. Using a knock-in mouse model of SCA1 that recapitulates the selective neurodegeneration seen in affected individuals, we found that elevated Atxn1l levels suppress neuropathology by displacing mutant Atxn1 from its native complex with Capicua (CIC). Our results provide genetic evidence that the selective neuropathology of SCA1 arises from modulation of a core functional activity of ATXN1, and they underscore the importance of studying the paralogs of genes mutated in neurodegenerative diseases to gain insight into mechanisms of pathogenesis.
"While wild type ataxin-1 shuttles back and forth between nucleus and cytoplasm, ataxin-1 with a poly-Q tract fails to properly transport back to the cytoplasm after entry into the nucleus . Although nuclear IB were identified as a pathological hall mark primarily in the affected brain regions, several studies suggest that the function of IB is neuroprotective [106, 107]. 14-3-3 β, ζ, and ε proteins bind to phosphorylated ataxin-1 and impede its translocation into the nucleus, prevent its dephosphorylation, and stabilize the protein . "
[Show abstract][Hide abstract] ABSTRACT: 14-3-3 proteins are abundantly expressed adaptor proteins that interact with a vast number of binding partners to regulate their cellular localization and function. They regulate substrate function in a number of ways including protection from dephosphorylation, regulation of enzyme activity, formation of ternary complexes and sequestration. The diversity of 14-3-3 interacting partners thus enables 14-3-3 proteins to impact a wide variety of cellular and physiological processes. 14-3-3 proteins are broadly expressed in the brain, and clinical and experimental studies have implicated 14-3-3 proteins in neurodegenerative disease. A recurring theme is that 14-3-3 proteins play important roles in pathogenesis through regulating the subcellular localization of target proteins. Here, we review the evidence that 14-3-3 proteins regulate aspects of neurodegenerative disease with a focus on their protective roles against neurodegeneration.
"Utilizing a SCA1 Drosophila model, Mizutani and colleagues showed that an eye defect, caused by mutant ATXN1, was suppressed by ATXN1L overexpression due to the association of both proteins . Moreover, evidence was provided that the activity of mutant ATXN1 causative for the observed neurotoxic events in a SCA1 knock-in mouse model can be ameliorated by duplication of ATXN1L modifying incorporation of mutant ATXN1 into native protein complexes . Consequently, it will be interesting to explore whether gene dosage compensation or antagonistic behavior between ATXN2L and ATXN2 might occur in SCA2 transgenic animal models and whether and how this impacts SCA2 pathogenesis. "
[Show abstract][Hide abstract] ABSTRACT: Paralogs for several proteins implicated in neurodegenerative disorders have been identified and explored to further facilitate the identification of molecular mechanisms contributing to disease pathogenesis. For the disease-causing protein in spinocerebellar ataxia type 2, ataxin-2, a paralog of unknown function, termed ataxin-2-like, has been described. We discovered that ataxin-2-like associates with known interaction partners of ataxin-2, the RNA helicase DDX6 and the poly(A)-binding protein, and with ataxin-2 itself. Furthermore, we found that ataxin-2-like is a component of stress granules. Interestingly, sole ataxin-2-like overexpression led to the induction of stress granules, while a reduction of stress granules was detected in case of a low ataxin-2-like level. Finally, we observed that overexpression of ataxin-2-like as well as its reduction has an impact on the presence of microscopically visible processing bodies. Thus, our results imply a functional overlap between ataxin-2-like and ataxin-2, and further indicate a role for ataxin-2-like in the regulation of stress granules and processing bodies.
PLoS ONE 11/2012; 7(11):e50134. DOI:10.1371/journal.pone.0050134 · 3.23 Impact Factor
"ATXN1 also interacts with two RNA-splicing factors, RBM17 (Lim et al., 2008) and U2AF65 (de Chiara et al., 2009). Two evolutionarily conserved regions within ATXN1 drive these interactions; the 120-amino acid AXH domain (de Chiara et al., 2003; Chen et al., 2004), which interacts with Capicua (Lam et al., 2006), Rora–Tip60 (Gehrking et al., 2011), Gfi-1 (Tsuda et al., 2005) and ATXN1L (Bowman et al., 2007), and a 12-amino acid segment, residues 768–780 toward the C terminus of ATXN1. This C-terminal segment contains three overlapping functional motifs and an endogenous site of phosphorylation at Ser776 (S776; Emamian et al., 2003; Huttlin et al., 2010). "
[Show abstract][Hide abstract] ABSTRACT: Ataxia is a neurological disorder characterized by loss of control of body movements. Spinocerebellar ataxia (SCA), previously known as autosomal dominant cerebellar ataxia, is a biologically robust group of close to 30 progressive neurodegenerative diseases. Six SCAs, including the more prevalent SCA1, SCA2, SCA3, and SCA6 along with SCA7 and SCA17 are caused by expansion of a CAG repeat that encodes a polyglutamine tract in the affected protein. How the mutated proteins in these polyglutamine SCAs cause disease is highly debated. Recent work suggests that the mutated protein contributes to pathogenesis within the context of its "normal" cellular function. Thus, understanding the cellular function of these proteins could aid in the development of therapeutics.
The Journal of Cell Biology 04/2012; 197(2):167-77. DOI:10.1083/jcb.201105092 · 9.83 Impact Factor
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