mRNA localisation and local translation in neurons support vital neuronal functions and homeostasis. Increasing transcriptomic and proteomic evidence in the past two decades reveals subsets of mRNAs differentially localised to and translated in neuronal compartments, and underlying mechanisms involved in RNA trafficking and local translational control. Due to technical limitations, it remains elusive how localisation and local translation of mRNA isoforms are spatiotemporally regulated. Taking advantages of the recently developed multi-omics technology, we explore how alternative splicing influences subcellular transcriptome and translatome in neurons, particularly in the axonal and synaptic compartments.
To maintain proteome homeostasis at the distal neuronal processes, local translatomes are dynamically remodelled in response to external stimuli, including chemical cues, acute stress and chronic diseases. Additionally, brain temperature fluctuation driven by circadian rhythm also acts as a recurring stimulus for neurons in human brains. Our team explore how temperature changes impact neuronal mRNA splicing, localisation and translation. In addition, we are interested in determining whether exposure to hypothermic temperatures (32-35°C), which offers profound neuroprotective effects, affects the synaptic transcriptome and translatome.
Synaptic loss is a frequent early manifestation of neurodegenerative disorders. Ample evidence, including our previous work, suggests that RNA localisation is altered and local protein synthesis is attenuated in disease models. Therefore, studying RNA metabolism in human neuron models may shed lights on early interventions of neurodegenerative disorders. By studying human iPSC-derived neuron and organoids, we examine if homeostasis of isoform-specific local translatomes is perturbed before synapse loss and neuron death.