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Answers to Sleep Disorder and new paradigm for treatment and mechanism of neurodegenerative disease

Researchers have identified a novel role of ATAXIN-2 as a posttranscriptional coactivator crucial for circadian behaviors and molecular clocks. The work was carried out by Chunghun Lim and colleagues during his post-doctoral time at Northwestern University.
ATAXIN-2 is a protein encoded by the ATXN2 gene conserved among different animal species. Mutations in human ATAXIN-2 gene have been implicated in neurodegenerative diseases such as spinocerebellar ataxia type 2 (SCA2), amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease after a famous baseball player in MLB), and Parkinson's disease. They show that ATAXIN-2 is a novel clock gene, which is important for sustaining robust circadian rhythms by coordinating translationally active protein complexes with a circadian translation factor TWENTY-FOUR.

The definition of a novel translational protein complex specific to circadian clock neurons as well as the first clear demonstration of a posttranscriptional coactivator function of ATAXIN-2 impacts on circadian clock mechanisms. Furthermore, their results provide important clues for molecular bases underlying the ATAXIN-2 dependent neurodegeneration.

Chunghun Lim, professor of the School of Nano-Bioscience and Chemical Engineering at the Ulsan National Institute of Science and Technology, was the key researcher in this work.

Circadian rhythms adaptively adjust internal biological clocks in animals to daily environmental changes. Chunghun Lim and Ravi Allada of Northwestern University in collaboration with Prof. Joonho Choe at the Korea Advanced Institute of Science and Technology (KAIST) previously showed that a novel Drosophila gene TWENTY-FOUR (TYF) activates PERIOD (PER) translation, one of the key clock genes, thereby maintaining rhythms in circadian behaviors.

In this study, Chunghun Lim and Ravi Allada took a proteomics approach to identify key factors important for TYF-dependent translation activation. They find a Drosophila homolog of human neurodegeneration gene ATAXIN-2 interacts with TYF. ATAXIN-2 binding domain is essential for TYF function in vivo. Moreover, depletion of ATAXIN-2 in the pacemaker neurons leads to impaired PER translation and poor behavioral rhythms similarly observed in TYF mutant flies.

The research data using in vitro cell cultures validate that depletion of ATAXIN-2 disrupts translationally active TYF protein complexes and suppresses TYF-dependent translation. In fact, ATAXIN-2 can directly activate translation from its associating mRNAs, strongly supporting that ATAXIN-2 is a critical post-transcriptional coactivator in TYF function.

“I believe our results could explain sleep disorders observed in SCA2 patients and will provide a new paradigm for understanding molecular pathogenesis and developing therapeutics of ATAXIN-2 related neurodegeneration diseases,” said Prof. Lim.
He also explained that one future plan will be to determine direct target mRNAs of ATAXIN-2 responsible for the pathogenesis in ATAXIN-2 dependent neurodegeneration and a long-term research goal will aim to more systematically screen for novel posttranscription factors involved in rhythmic circadian behaviors and neurodegeneration.

The research was supported by The National Institute of Neurological Disorders and the Defense Advanced Research Projects Agency.

A description of the new research has been published in the Science, world leading science journal, on May 16, 2013. (Title: ATAXIN-2 Activates PERIOD Translation to Sustain Circadian Rhythm in Drosophila.)

Ulsan National Institute of Science and Technology
Homepage of Chunghun Lim:
Journal information
Funding information
The National Institute of Neurological Disorders and the Defense Advanced Research Projects Agency

Eunhee Song | Research asia research news
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