Our lab is interested in the molecular mechanisms that regulate subcellular RNA localization, translation, and stability in neurons and neurodegeneration and the roles of RNA binding proteins (RBPs) and miRNAs in these processes. We combine systems biology, biochemical, and imaging approach to analyze subcellular RNA localization. Thus, we developed a compartmentalized neuronal culture that allows the separation of subcellular compartments – cell bodies and neurites - combined with proteomics, RNA-seq, Ribo-seq, and bioinformatic analyses (spatial omics; Zappulo et al., 2017; Ludwik et al. 2019). Using this approach, we demonstrated that alternative 3'UTR isoforms direct the localization of functionally distinct alternative protein isoforms to different neuronal compartments (Ciolli Mattioli et al., 2019).

 

By identifying a conserved set of mRNAs that localize to neurites across multiple neuronal types and species, we created an essential resource for future hypothesis-driven research (von Kugelgen and Chekulaeva, 2020).

 

Our work on miRNAs showed that the mechanism of miRNA silencing has been conserved across 600 million years of animal evolution (Mauri et al., 2016).

 

In addition, we are applying our expertise to understand how RNA localization is affected in neurodegeneration. To this end, we have generated a biobank of hiPSC lines from fibroblasts of ALS patients. We are applying spatial omics to understand how local RNA metabolism may be malfunctioning in motor neurons differentiated from ALS patient-derived hiPSCs.

 

We have also dissected the mechanism of translational repression in Charcot–Marie–Tooth (CMT) disease that causes degeneration of motor and sensory neurons (Mendonsa et al, 2021). Using high-resolution ribosome profiling and interaction studies, we showed that CMT mutations in glycyl-tRNA synthetase deplete the pool of glycyl-tRNAᴳˡʸ available for translation and cause ribosomes to pause at glycine codons, which in turn activates the integrated stress response (ISR).

 

Our more recent work on SARS-CoV-2 showed how the virus uses the same protein NSP1 to inhibit the expression of host genes while enhancing that of viral RNA.

 

In summary, our research focuses on the biochemical mechanisms of subcellular RNA localization and local translation in neurons, their link to neurodegenerative disorders and applies a combination of systems biology, biochemical and imaging approaches on stem cell-derived and primary neurons.

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