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- Title
Frontotemporal Lobar Dementia Mutant Tau Impairs Axonal Transport through a Protein Phosphatase 1γ-Dependent Mechanism.
- Authors
Combs, Benjamin; Christensen, Kyle R.; Richards, Collin; Kneynsberg, Andrew; Mueller, Rebecca L.; Morris, Sarah L.; Morfini, Gerardo A.; Brady, Scott T.; Kanaan, Nicholas M.
- Abstract
Pathologic 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 evaluated interactions of wild-type or mutant tau with specific PP1 isoforms (α,β and γ) to examine how the interaction contributes to this toxic effect using primary rat hippocampal neurons from both sexes. Pull-down and bioluminescence resonance energy transfer experiments revealed selective interactions of wild-type tau with PP1a and PP1c isoforms, but not PP1b, 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 PP1c, but not PP1a, 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 PP1c-dependent pathway that disrupts axonal transport in neurons.
- Subjects
FRONTOTEMPORAL lobar degeneration; AXONAL transport; PHOSPHOPROTEIN phosphatases; CARRIER proteins; FRONTOTEMPORAL dementia; TAU proteins
- Publication
Journal of Neuroscience, 2021, Vol 41, Issue 45, p9431
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.1914-20.2021