Microtubule stability, Golgi organization, and transport flux require dystonin‐a2/MAP1B interaction

Loss of function of dystonin cytoskeletal linker proteins causes neurodegeneration in dystonia musculorum ( dt ) mutant mice. While much investigation has focused on understanding dt pathology, divergent functions of dystonin isoforms remain unclear. Here, we highlight novel functions of the dystonin‐a2 isoform in mediating microtubule (MT) stability, Golgi organization, and flux through the secretory pathway. Using dystonin mutant mice combined with isoform‐specific loss of function analysis, we find dystonin‐a2 is bound to MT associated protein 1B (MAP1B) in the centrosomal region, where it maintains MT acetylation. In dt neurons, absence of the MAP1B/dystonin‐a2 interaction results in altered MAP1B perikaryal localization, leading to MT deacetylation and instability. Deacetylated MTs result in Golgi fragmentation and prevent anterograde trafficking via motor proteins. Maintenance of MT acetylation through trichostatin A (TSA) administration or MAP1B overexpression in vitro , mitigates the observed defect. These aberrations are apparent in pre‐phenotype dorsal root ganglia (DRG) and primary sensory neurons, suggesting they are causal in the dt disorder.