Open Close
Reference
Citation
Ishiguro, T., Sato, N., Ueyama, M., Fujikake, N., Sellier, C., Kanegami, A., Tokuda, E., Zamiri, B., Gall-Duncan, T., Mirceta, M., Furukawa, Y., Yokota, T., Wada, K., Taylor, J.P., Pearson, C.E., Charlet-Berguerand, N., Mizusawa, H., Nagai, Y., Ishikawa, K. (2017). Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31.  Neuron 94(1): 108--124.e7.
FlyBase ID
FBrf0235231
Publication Type
Research paper
Abstract

Microsatellite expansion disorders are pathologically characterized by RNA foci formation and repeat-associated non-AUG (RAN) translation. However, their underlying pathomechanisms and regulation of RAN translation remain unknown. We report that expression of expanded UGGAA (UGGAAexp) repeats, responsible for spinocerebellar ataxia type 31 (SCA31) in Drosophila, causes neurodegeneration accompanied by accumulation of UGGAAexp RNA foci and translation of repeat-associated pentapeptide repeat (PPR) proteins, consistent with observations in SCA31 patient brains. We revealed that motor-neuron disease (MND)-linked RNA-binding proteins (RBPs), TDP-43, FUS, and hnRNPA2B1, bind to and induce structural alteration of UGGAAexp. These RBPs suppress UGGAAexp-mediated toxicity in Drosophila by functioning as RNA chaperones for proper UGGAAexp folding and regulation of PPR translation. Furthermore, nontoxic short UGGAA repeat RNA suppressed mutated RBP aggregation and toxicity in MND Drosophila models. Thus, functional crosstalk of the RNA/RBP network regulates their own quality and balance, suggesting convergence of pathomechanisms in microsatellite expansion disorders and RBP proteinopathies.

PubMed ID
PubMed Central ID
PMC5681996 (PMC) (EuropePMC)
Related Publication(s)
Note

SCA31 Flies Perform in a Balancing Act between RAN Translation and RNA-Binding Proteins.
Jackson, 2017, Neuron 94(1): 4--5 [FBrf0235294]

Associated Information
Comments
Associated Files
Other Information
Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Neuron
    Title
    Neuron
    Publication Year
    1988-
    ISBN/ISSN
    0896-6273
    Data From Reference