Objective: To investigate the role of RNA binding protein Elavl in Parkinson’s disease related adaptive changes in the striatal transcriptome.

Background: Elav-like (Elavl or Hu) proteins are RNA binding proteins first described as immune targets in  paraneoplastic neurologic syndromes(1). Elavl proteins bind to U-rich regions of their RNA targets to affect mRNA stability and alternative splicing (2). Three of the four Elavl paralogs (Elavl2, Elavl3 and Elavl4) are expressed exclusively in neurons. Multiple GWAS studies have linked Elavl to Parkinson’s disease (3-5). Elavl3 knockout mice exhibit tremor, ataxia  and abnormal postural reflexes (6). Here, by combining studies in transgenic mice that allow us to identify cell-type specific regulation of gene expression, and post-mortem human striatal tissue, we investigate the role of Elavl in Parkinson’s disease.

Method: We have generated a knock-in mice targeting the endogenous Elavl3 locus to  conditionally express AcGFP-tagged Elavl3 in a cre-dependent manner. HITS-CLIP was performed as previously described in mice and human brain samples(7).

Results: Immunofluorescence studies in mouse brains which conditionally express AcGFP-tagged Elavl3 show that relative to other brain areas, Elavl3 is highly expressed in the striatum, in both Drd1 and Drd2 medium spiny neurons. To identify the RNA targets of Elavl3, we performed Elavl3-AcGFP high-throughput crosslinking and immunoprecipitation (HITS-CLIP) in mice conditionally expressing Elavl3 in Drd1 or Drd2 neurons. HITS-CLIP followed by Gene Ontology analysis showed that Elavl3 targets gene transcripts important for synaptic plasticity. Transcriptome analyses of Elavl3 knockout striatum show that levels of Elavl3 bound RNA’s are indeed altered, thus confirming that these are functional targets. Using published datasets of transcriptome changes in Drd1 and Drd2 neurons in Parkinson’s disease and levodopa induced dyskinesia animal models, we demonstrate that Elavl3 targets are enriched in the downregulated striatal transcriptome (8). We further identify Elavl targets in human brain and compare target transcriptomes in control and Parkinson’s disease striatum.

Conclusion: We show that in striatal medium spiny neurons, Elavl3, an RNA binding protein, regulates synaptic plasticity related gene transcripts, and could play an important role in Parkinson’s disease, in which striatal synaptic plasticity is known to be altered.

References: 1. Szabo A, et al. (1991) HuD, a paraneoplastic encephalomyelitis antigen, contains RNA-binding domains and is homologous to Elav and Sex-lethal. Cell 67(2):325-333. 2. Ince-Dunn G, et al. (2012) Neuronal Elav-like (Hu) proteins regulate RNA splicing and abundance to control glutamate levels and neuronal excitability. Neuron 75(6):1067-1080. 3. Noureddine MA, et al. (2005) Association between the neuron-specific RNA-binding protein ELAVL4 and Parkinson disease. Hum Genet 117(1):27-33. 4. DeStefano AL, et al. (2008) Replication of association between ELAVL4 and Parkinson disease: the GenePD study. Hum Genet 124(1):95-99. 5. Haugarvoll K, et al. (2007) ELAVL4, PARK10, and the Celts. Mov Disord 22(4):585-587. 6. Ogawa Y, et al. (2018) Elavl3 is essential for the maintenance of Purkinje neuron axons. Sci Rep 8(1):2722. 7. Licatalosi DD, et al. (2008) HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456(7221):464-469. 8. Heiman M, et al. (2014) Molecular adaptations of striatal spiny projection neurons during levodopa-induced dyskinesia. Proc Natl Acad Sci U S A 111(12):4578-4583.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/rna-binding-protein-mediated-regulation-of-striatal-transcriptome-in-parkinsons-disease/