Spatial Dysregulation of mRNA at the Peripheral Neuro-Glial Interface in ALS

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease driven by dysfunction of the RNA-binding protein TDP-43, whose early pathology emerges in axons and neuromuscular junction (NMJ) synapses at the neuronal periphery, preceding hallmark TDP-43 aggregation. Although its splicing function is well-characterised, TDP-43 also mediates mRNA trafficking and local translation essential for motoneuron and glial function at the NMJ. However, how TDP-43 dysfunction perturbs peripheral RNA-metabolism and initiates early NMJ degeneration remains poorly understood. I recently discovered that peripherally-localised glial/neuronal NMJ mRNAs are highly-enriched for ALS-risk genes, notably glutamate homeostasis and cell-contact regulators. Importantly, their glial-specific expression directly influences adjacent motoneuron plasticity. Therefore, I hypothesise that TDP-43 mutations disrupt peripheral mRNA localisation at the NMJ, triggering synaptic instability and neuro-glial miscommunication. I propose to use versatile Drosophila ALS models to: (1) Map transcriptome-wide mRNA mislocalisation and local translation changes at the motoneuron/glial periphery; (2) Dissect the molecular basis of TDP-43’s mRNA target choice and transport granule assembly at the NMJ; (3) Determine how ALS-induced mRNA mislocalisation disrupts synaptic function, neuro-glial communication and organismal behaviours. This research will establish a mechanistic framework for TDP-43-mediated peripheral RNA dysregulation in ALS, and support its extension to mammalian models in my future independent research.