Prof. Hitoshi Okazawa

Prof. Okazawa
ISP2012 Symposium Talk Abstract:

Pathomechanisms of Intellectual Disabilities linked to a new RNA splicing protein, PQBP1

We previously discovered a novel gene, polyglutamine tract-binding protein-1 (PQBP1) as a mediator of polyglutamine disease pathology (Waragai et al., Hum Mol Genet 1999; Okazawa et al., Neuron 2002). PQBP1 interacts with multiple polyglutamine diseases proteins including ataxin-1 and huntingtin. PQBP1 possesses a unique C-terminal domain (CTD) and a WW domain (WWD) conserved beyond species (C. elegans, Drosophila and Arabidopsis). PQBP1 interacts with a component of U5 spliceosome, U5-15kD via CTD and another RNA binding protein WBP11/NpwBP/SIPP via WWD. Mass spectrometry analysis revealed that PQBP1 is transiently involved in spliceosome at the critical step for exon-intron junction recognition.

European Consortium of X-linked Mental Retardation/ Intellectual Disability (MR/ID) identified that PQBP1 is a causative gene for non-syndromic ID and syndromic ID including Renpenning syndrome, Golabi-Ito-Hall syndrome and Sutherland-Haan syndrome. Recent analyses revealed the patient frequency among population is comparable to Rett syndrome, indicating the clinical significance of PQBP1.

We have investigated PQBP1 via multiple approaches, and found interacting partner molecules of PQBP1 (Waragai et al., BBRC 2000; Okazawa et al., Neuron 2002), revealed an intrinsically unstructured nature of CTD (Takahashi et al., BBA 2009, 2010), and made various animal models. Drosophila mutant of PQBP1 showed a defect in learning acquisition, which is caused by reduced expression of NR1 subunit of NMDA receptor in projection neurons (Tamura et al., J Neurosci. 2010).  Correspondingly, knock down mouse model of PQBP1 showed anxiety-related cognitive impairment and reduced expression of NR1 (Ito et al., Hum Mol Genet 2009). An HDAC inhibitor, PBA recovered these phenotypes in both models. Meanwhile, overexpression of PQBP1 cause delayed degeneration of spinal motoneurons in mouse (Okuda et al., Hum Mol Genet 2003) and lifespan shortening in Drosophila.

We recently generated conditional KO mouse models of PQBP1, and performed systemic analysis of gene expression profiles. I will talk about new mechanisms underlying PQBP1-linked ID unraveled through these analyses.

Prof. Okazawa's ISP2012 Profile
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ISP2012 Abstracts