Several studies are underway in the RNA Regulation Section to investigate the RBPs and ncRNAs that influence neuronal physiology and pathology, with particular emphasis on neurodegeneration. During this review period, we have studied the role of several RBPs and ncRNAs implicated in Alzheimers disease (AD) and Parkinsons disease (PD), as well as other pathologies of the nervous system. We recently reported that the levels of amyloid precursor protein (APP), which is cleaved to release the Alzheimers disease hallmark peptide A, was regulated by RBPs FMRP (fragile X mental retardation protein) and hnRNP C (heterogeneous nuclear ribonucleoprotein C). We further discovered that FMRP and hnRNPC associated with the coding region of APP mRNA in a competitive manner and repressed or enhanced APP translation, respectively. Expanding upon this work, we collaborated with Weidong Wangs group (LG, NIA), in studies that revealed that FMRP function was modulated by a novel RNA topoisomerase activity Xu et al., Nat. Neurosci 2013. We have also continued collaborative studies with the Cookson laboratory (LNG, NIA), aimed at elucidating the function of the Parkinsons disease-associated protein DJ-1. Prominent among DJ-1 target mRNAs were those encoding proteins that regulate mitochondrial metabolism. During this review period, we have continued to study the RBP HuD, which is found primarily in neuronal tissues and was negatively regulated by the microRNA miR-375. Further studies have focused on other cell types in the nervous system;for example, in collaboration with the Woodhoo lab (BioGune, Spain), we reported that the HuD-related protein HuR was linked to development of Schwann cells Iruarrizaga-Lejarreta et al., J. Neuroscience, 2012 and in collaboration with the Mattson lab (LNS, NIA), miR-181 was identified as a key mediator in the neuroinflammatory response of astrocytes Hutchison et al., 2013.
|Yoon, Je-Hyun; Gorospe, Myriam (2014) Ribonucleoprotein therapy in Alzheimer's disease? Aging (Albany NY) 6:428-9|
|Kang, Min-Ju; Abdelmohsen, Kotb; Hutchison, Emmette R et al. (2014) HuD regulates coding and noncoding RNA to induce APP?A? processing. Cell Rep 7:1401-9|
|Xu, Dongyi; Shen, Weiping; Guo, Rong et al. (2013) Top3* is an RNA topoisomerase that works with fragile X syndrome protein to promote synapse formation. Nat Neurosci 16:1238-47|
|Hutchison, Emmette R; Kawamoto, Elisa M; Taub, Dennis D et al. (2013) Evidence for miR-181 involvement in neuroinflammatory responses of astrocytes. Glia 61:1018-28|