Objective: This work investigates motor phenotypes and neurochemical changes in a mouse model of tauopathy linked to tau mis-splicing. We sought to validate a potential therapeutic intervention to preclude disease progression.

Background: The microtubule-associated protein TAU controls neuronal functions such as microtubule dynamics and axonal transport. The alternative splicing of tau primary transcript produces isoforms with 3 or 4 microtubule binding repeats (3R and 4R), in equal amounts in the normal adult human [1]. Tauopathies are neurodegenerative diseases, with presence of insoluble tau aggregates and loss of tau function. In tauopathies with movement disorders, such as Progressive Supranuclear Palsy (PSP) the endogenous 3R:4R tau balance is altered. Here we investigated motor phenotypes and neurochemical changes in the basal ganglia of a mouse model linked to tau mis-splicing and assessed potential strategies to restore tau isoforms balance.

Methods: Transgenic mice bearing 3R:4R imbalance (Htau mice), and their wild type and Tau knock-out controls were tested in the open field and rotarod to assess motor coordination. Cognitive performance was tested in the novel object recognition (NOR) task. Western blot and immunohistochemistry were performed to assess tau pathology in the basal ganglia. Finally, a trans-splicing RNA reprogramming strategy [2] was used to modulate the 3R:4R tau ratio in young htau mice and phenotypic rescue was assessed after treatment.

Results: Both TauKO and htau mice showed poor performance in the rotarod compared to WT mice. Cognitive tasks were also severely impaired in aged htau model. Analysis of tau isoforms contents indicated that 3R >4R tau in the PFC and striatum of htau, yet, tau deposits were detected in the cortex but not in the striatum. Trans-splicing rescue of tau isoforms imbalance in the PFC and striata of young mice precluded cognitive impairment and motor deficits. In addition, local modulation of isoforms balance reduced insoluble and hyperphosphorylated tau contents.

Conclusions: Either lack of tau function or tau isoforms imbalance are detrimental for motor activity, however our results evidence that the (dys) functional consequences of tau 3R:4R imbalance would have a stronger impact in the development of motor and cognitive impairments than mutations that induce the lack of function. In addition the results obtained using tau isoforms modulation in the htau model rise the potential use of RNA reprogramming to correct tau mis-splicing in human tauopathies.

References: 1. Spillantini MG, Goedert M (2013) Tau pathology and neurodegeneration. Lancet Neurol 12:609–622. 2. Avale ME, Rodríguez-Martín T, Gallo JM (2013) Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing. Hum Mol Genet 22:2603–2611.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/motor-and-cognitive-deficits-in-a-mouse-model-of-tauopathy-with-tau-isoforms-imbalance-potential-therapeutic-strategies/