Home
This Title All WIREs
WIREs RSS Feed
How to cite this WIREs title:
WIREs RNA
Impact Factor: 4.928

Ataxin‐2: A versatile posttranscriptional regulator and its implication in neural function

Full article on Wiley Online Library:   HTML PDF

Can't access this content? Tell your librarian.

Ataxin‐2 (ATXN2) is a eukaryotic RNA‐binding protein that is conserved from yeast to human. Genetic expansion of a poly‐glutamine tract in human ATXN2 has been implicated in several neurodegenerative diseases, likely acting through gain‐of‐function effects. Emerging evidence, however, suggests that ATXN2 plays more direct roles in neural function via specific molecular and cellular pathways. ATXN2 and its associated protein complex control distinct steps in posttranscriptional gene expression, including poly‐A tailing, RNA stabilization, microRNA‐dependent gene silencing, and translational activation. Specific RNA substrates have been identified for the functions of ATXN2 in aspects of neural physiology, such as circadian rhythms and olfactory habituation. Genetic models of ATXN2 loss‐of‐function have further revealed its significance in stress‐induced cytoplasmic granules, mechanistic target of rapamycin signaling, and cellular metabolism, all of which are crucial for neural homeostasis. Accordingly, we propose that molecular evolution has been selecting the ATXN2 protein complex as an important trans‐acting module for the posttranscriptional control of diverse neural functions. This explains how ATXN2 intimately interacts with various neurodegenerative disease genes, and suggests that loss‐of‐function effects of ATXN2 could be therapeutic targets for ATXN2‐related neurological disorders. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
Molecular structure and conservation of Ataxin‐2 (ATXN2). (a) Schematic diagram of ATXN2 homologs, their protein sizes in amino acids, and conserved domains. Poly‐Q, polyglutamine tract; Lsm, like‐sm domain; LsmAD, Lsm‐associated domain; PAM2, PABP‐interacting motif 2. Mutational expansion of the poly‐Q tract in human ATXN2 has been implicated in neurodegenerative diseases. However, the relative location of human poly‐Q is not conserved in other ATXN2 homologs. (b) Relative sequence homology (%) of ATXN2 homologs. Note that the overall sequence homology of ATXN2 homologs is weak but their functional domains are well conserved. Lsm for RNA‐binding; Lsm and LsmAD for binding to LSM12 and DDX6 proteins; PAM2 for PABP‐binding. (c) Multiple sequence alignments of PAM2 sequences in ATXN2 homologs. Note that yeast ATXN2 does not contain PAM2 but the molecular interaction between ATXN2 and PABP has been also demonstrated in yeast
[ Normal View | Magnified View ]
Ataxin‐2 (ATXN2)‐dependent regulation of cellular physiology and its implication in neural function. ATXN2 contributes to the formation of stress‐induced cytoplasmic granules (e.g., stress granules) as well as pathogenic inclusions in neurodegenerative conditions. In addition, ATXN2 regulates mTORC1 and MAPK signaling pathways, and is likely involved in a range of cellular processes from cap‐dependent translation to autophagy, lipid homeostasis, and branched‐chain amino acid (BCAA) metabolism. Obesity, fatty livers, and altered lipid metabolism have been well documented in ATXN2 knock‐out mice. However, molecular and neural substrates of ATXN2 relevant to these metabolic phenotypes remain to be defined
[ Normal View | Magnified View ]
Posttranscriptional activity of Ataxin‐2 (ATXN2) and its implication in neural function. Genetic studies in cell cultures and model organisms have uncovered different aspects of molecular functions of ATXN2 and their associating proteins. These include RNA‐binding, mRNA stabilization, translational activation, poly‐A tailing, and miRNA‐dependent gene silencing
[ Normal View | Magnified View ]

Browse by Topic

RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA in Disease and Development > RNA in Disease

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

The latest WIREs articles in your inbox

Sign Up for Article Alerts