Dysfunction of the Microtubule Associated Protein TAUin Motor and Cognitive Impairments: A PotentialMolecular Therapy for Tauopathies

ESPINDOLA, SONIA; ANA DAMIANICH; FERRARIO, JUAN ESTEBAN; AVALE, MARIA ELENA (CORRESPONSAL); SARTOR MANUELA

Miami

Congreso; PAN American Congress-Movement Disorders Society; 2018

Movement Disroders Society

Objectives: This work aimed to investigate cognitive and motor phenotypes, and neurochemical changes in the basal ganglia 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 is crucially involved in 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), present in equal amounts in the normal adult human [1]. Tauopathies are a group of neurodegenerative diseases, with presence of insoluble tau aggregates and loss of tau function. Several tauopathies such as Frontotemporal dementia and Progressive Supranuclear Palsy (PSP) affect the basal ganglia thus leading PD symptoms. In those pathologies the endogenous 3R:4R tau balance is frequently altered, due to genetic or epigenetic mechanisms [2]. For translational studies, mouse models reflecting deficits in tau splicing are essential to evaluate potential therapeutic interventions for those tauopathies. Here we investigated motor phenotypes and neurochemical changes in the basal ganglia of a mouse model of tauopathy linked to tau mis-splicing to assess potential therapeutic interventions.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 [3] was used to modulate the 3R:4R tau ratio in young htau mice, by estreotaxic injection of lentiviral vectors and phenotypic rescue was assessed after 6 months of 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. htau brain analysis of tau isoforms contents indicated that 3R >4R tau in the PFC and striatum. Although tau deposits were detected in the cortex but not in the striatum of htau mice. Rescue of tau isoforms imbalance by trans-splicing in young mice precluded cognitive impairment and motor deficits in the htau model. In addition, local modulation of isoforms balance reduced insoluble and hyperphosphorylated tau contents.Conclusions: Either lack of tau function or tau isoforms imbalance (gain of toxic function) 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.