Abstract:
Peripheral neurons depend on a highly organised microtubule cytoskeleton to maintain their structural integrity and facilitate intracellular transport. Variations in microtubule organization which dictates its specific functions across different neuronal compartments is governed via the tubulin code, a regulatory system composed of tubulin isotypes and their post-translational modifications. Chemotherapeutic agents like Bortezomib disrupt this homeostasis which leads to Bortezomib-Induced Peripheral Neuropathy (BIPN). Clinically, BIPN presents as a painful, length-dependent “dying back” axonopathy that preferentially affects small and unmyelinated sensory fibres. This study investigates the effects of BTZ on neuronal microtubules which might lead to degeneration in these neurons.
Utilizing adult mouse primary DRG cultures, we demonstrate that exposure to 100 nM BTZ induces axonal fragmentation. Consistent with this, we observed accumulation of PTMs like acetylated, detyrosinated and Δ2-tubulin. To further understand, we examined the spatial distribution of these PTMs in the soluble tubulin pool and the polymerised microtubule lattice. We observed a preferential enrichment of acetylated tubulin on the polymerised lattice following BTZ exposure. Concurrently, total detyrosinated and Δ2-tubulin levels increased without altering the balance between soluble tubulin pool and polymerised lattice which reflects BTZ’s dual role in impairing proteasomal clearance and promoting tubulin polymerisation. We hypothesize that BTZ-induced alterations in PTM levels disrupt the essential interactions between microtubules and its associated regulatory proteins.
