FTLD mutant tau impairs axonal transport through a protein phosphatase 1γ-dependent mechanism.

Pathological tau modifications are characteristic of Alzheimer’s disease and related dementias, but mechanisms of tau toxicity continue to be debated. Inherited mutations in tau cause early-onset frontotemporal lobar dementias (FTLD-tau) and are commonly used to model mechanisms of tau toxicity in tauopathies. Previous work in the isolated squid axoplasm model demonstrated that several pathogenic forms of tau inhibit axonal transport through a mechanism involving activation of protein phosphatase 1 (PP1). Here, we determined that P301L and R5L FTLD mutant tau proteins elicit a toxic effect on axonal transport as monomeric proteins. We also evaluated interactions between wild type and mutant tau with specific PP1 isoforms (α, β and γ), further examining their contribution to this toxic effect using primary rat hippocampal neurons from both sexes. Pulldown and bioluminescence resonance energy transfer experiments revealed selective interactions of wild type tau with PP1α and PP1γ isoforms, but not PP1β, which were significantly increased by the P301L tau mutation. The results from proximity ligation assays confirmed the interaction in primary hippocampal neurons. Moreover, expression of FTLD-linked mutant tau in these neurons enhanced levels of active PP1, also increasing the pausing frequency of fluorescently-labeled vesicles in both anterograde and retrograde directions. Knockdown of PP1γ, but not PP1α, rescued the cargo-pausing effects of P301L and R5L tau, a result replicated by deleting a phosphatase-activating domain in the amino terminus of P301L tau. These findings support a model of tau toxicity involving aberrant activation of a specific PP1γ-dependent pathway that disrupts axonal transport in neurons. Significance Statement Tau pathology is closely associated with neurodegeneration in Alzheimer’s disease and other tauopathies, but its toxic mechanisms remain a debated topic. We previously proposed that pathological tau forms induce dysfunction and degeneration through aberrant activation of a protein phosphatase 1 (PP1)-dependent pathway that disrupts axonal transport. Here, we show that tau directly interacts with specific PP1 isoforms, increasing levels of active PP1. Pathogenic tau mutations enhance this interaction, further increasing active PP1 levels and impairing axonal transport in isolated squid axoplasm and primary hippocampal neurons. Mutant tau-mediated impairment of axonal transport was mediated by PP1γ and a phosphatase-activating domain located at tau’s amino terminus. This work has important implications for understanding and potentially mitigating tau-mediated neurotoxicity in tauopathies.