TY - JOUR T1 - Two neuronal models of TDP-43 proteinopathy display reduced axonal translation, increased oxidative stress, and defective exocytosis JF - bioRxiv DO - 10.1101/2023.05.17.540919 SP - 2023.05.17.540919 AU - Alessandra Pisciottani AU - Laura Croci AU - Fabio Lauria AU - Chiara Marullo AU - Elisa Savino AU - Alessandro Ambrosi AU - Paola Podini AU - Marta Marchioretto AU - Filippo Casoni AU - Ottavio Cremona AU - Stefano Taverna AU - Angelo Quattrini AU - Jean-Michel Cioni AU - Gabriella Viero AU - Franca Codazzi AU - G. Giacomo Consalez Y1 - 2023/01/01 UR - http://biorxiv.org/content/early/2023/05/26/2023.05.17.540919.abstract N2 - Amyotrophic lateral sclerosis (ALS) is a progressive, lethal neurodegenerative disease mostly affecting people around 50-60 years of age. TDP-43, a ubiquitously expressed RNA-binding protein involved in pre-mRNA splicing and controlling mRNA stability and translation, forms neuronal cytoplasmic inclusions in an overwhelming majority of ALS patients, of both sporadic and familial origin, a phenomenon referred to as TDP-43 proteinopathy. These cytoplasmic aggregates disrupt the subcellular transport and localization of mRNA. The axon, like dendrites, is a site of mRNA translation, permitting the local synthesis of selected proteins, both constitutively and in response to stimuli reaching the axon and presynaptic terminal. This is especially relevant in upper and lower motor neurons, whose axon spans long distances, likely accentuating their susceptibility to ALS-related noxae. In this work we have generated and characterized two models of TDP-43 proteinopathy, consisting of virtually pure populations of mouse cortical neurons expressing a human TDP-43 fusion protein, wt or mutant, which accumulates as cytoplasmic aggregates. Neurons expressing human TDP-43 exhibit a global impairment in axonal protein synthesis, an increase in oxidative stress, and defects in presynaptic function and electrical activity. These changes correlate with deregulation in the axonal levels of polysome-engaged mRNAs playing relevant roles in those processes. Our data support the emerging notion that deregulation of mRNA metabolism and of axonal mRNA transport may trigger the dying-back neuropathy that initiates motor neuron degeneration in ALS.Competing Interest StatementThe authors have declared no competing interest. ER -