Abnormal metabolism of the microtubule-associated protein Tau is a key pathological mechanism underlying several neurodegenerative diseases, named tauopathies. Several neuropathological phenotypes are defined according to the specific brain nuclei and cell types affected, as well as the Tau isoforms present in pathological deposits. Progressive Supranuclear Palsy (PSP) is a primary tauopathy classified as an atypical parkinsonian syndrome, mainly affecting the basal ganglia and leading to motor impairment. In this study, we use the htau mouse model of tauopathy, in which the presence of pathological tau leads to striatal dysfunction and motor coordination deficits (Damianich et al 2021). We propose here a molecular therapy based on site directed expression of artificial microRNAs (Tau-miRNAs) to reduce pathological tau and thus improve motor phenotypes. Tau-miRNAs were delivered into the striatum at 6 months old- close to the onset of motor coordination deficit. Tau-miRNA treatment reduced motor coordination impairments in the rotarod at 12 months-old. Ongoing molecular analyses will further demonstrate if this improvement is related to tau reduction.