Lost in local translation: TDP-43 and FUS in axonal/neuromuscular junction maintenance and dysregulation in amyotrophic lateral sclerosis

Abstract

Key early features of amyotrophic lateral sclerosis (ALS) are denervation of neuromuscular junctions and axonal degeneration. Motor neuron homeostasis relies on local translation through controlled regulation of axonal mRNA localization, transport, and stability. Yet the composition of the local transcriptome, translatome (mRNAs locally translated), and proteome during health and disease remains largely unexplored. This review covers recent discoveries on axonal translation as a critical mechanism for neuronal maintenance/survival. We focus on two RNA binding proteins, transactive response DNA binding protein-43 (TDP-43) and fused in sarcoma (FUS), whose mutations cause ALS and frontotemporal dementia (FTD). Emerging evidence points to their essential role in the maintenance of axons and synapses, including mRNA localization, transport, and local translation, and whose dysfunction may contribute to ALS. Finally, we describe recent advances in omics-based approaches mapping compartment-specific local RNA and protein compositions, which will be invaluable to elucidate fundamental local processes and identify key targets for therapy development.

Keywords: ALS; FUS; NMJ; TDP-43; amyotrophic lateral sclerosis; axonal local translation; motor axon; neuromuscular junction; proteomics; scRNA-seq; spatial omics; translatome.