Knockout of Rab27b exacerbates neuropathology in alpha-synuclein mouse models

mice did not alter motor behavior or survival. However, Rab27b knockout increased proteinase-K resistant αsyn in the cortex, striatum, and substantia nigra of A53T mice starting as early as six months of age. Additionally, Rab27b KO increased phosphorylated S129 αsyn in the cortex and nigra. Astrocyte and microglial activation were also observed upon Rab27b KO in the A53T model. In the AAV αsyn model, Rab27b KO resulted in dopaminergic cell loss in the nigra, which was not observed in WT mice. Collectively, we report that loss of Rab27b results in elevated neuropathology in PD-relevant brain regions, validating its role as a therapeutic target in synucleinopathies.