Tau mis-splicing correlates with motor impairments and striatal dysfunction in a model of tauopathy

Abstract

Tauopathies are neurodegenerative diseases caused by the abnormal metabolism of the microtubule associated protein Tau, which is highly expressed in neurons and critically involved in microtubule dynamics. In the adult human brain, the alternative splicing of exon 10 in tau pre-mRNA produces equal amounts of protein isoforms with either three (3 R) or four (4 R) microtubule binding domains. Imbalance in the 3 R : 4 R tau ratio is associated with primary tauopathies that develop atypical parkinsonism, such as Progressive Supranuclear Palsy and Corticobasal Degeneration. Yet, the development of effective therapies for those pathologies is an unmet goal. Here we report motor coordination impairments in the htau mouse model of tauopathy which bear abnormal 3 R : 4 R tau isoforms contents, and contrariwise to TauKO mice, are unresponsive to L-DOPA. Preclinical-PET imaging, array tomography and electrophysiological analyses pointed the dorsal striatum as the candidate structure mediating such phenotypes. Indeed, local modulation of tau isoforms by RNA trans-splicing in the striata of adult htau mice, prevented motor coordination deficits and restored basal neuronal firing. Together, these results constitute readout that abnormal striatal tau-isoforms contents might lead to parkinsonian-like phenotypes and provide proof of concept that modulation of tau mis-splicing could be a plausible disease-modifying therapy for some primary tauopathies.

High altitude is associated with pTau deposition, neuroinflammation, and myelin loss

“…Furthermore, the observed higher levels of pTau were associated with variable levels of total Tau (HT7) across the different brain regions examined. Such hyperphosphorylated-tau/total-Tau ratio changes are not actually novel and have been observed in several Tau-related neurodegenerative conditions 39 , 40 . Generally, hyperphosphorylated-Tau/total-Tau ratio changes are considered to be part of molecular pathomechanisms associated with early neuronal dysfunctions as well as with cognitive and behavioral clinical abnormalities affecting specific neuronal types 25 , 41 – 43 .…”

SMaRT modulation of tau isoforms rescues cognitive and motor impairments in a preclinical model of tauopathy

“…In previous reports (Espíndola et al, 2018;Damianich et al, 2021) we showed that local modulation of 3R:4R tau isoforms contents into the mPFC or the striatum of htau mice could prevent cognitive or motor coordination deficits, when such modulation was performed at 3 months old, before phenotypic onset. Hence, the most relevant question we aimed to address in this study was if these phenotypes could be rescued, once the deficits were already present.…”

“…We have previously shown that the SMaRT strategy -spliceosome mediated RNA trans -splicing- ( Rodriguez-Martin et al, 2005 ) is a suitable tool to modulate E10 inclusion in endogenous MAPT transcript, both in mouse and human neurons in culture ( Avale et al, 2013 ; Lacovich et al, 2017 ), and into the adult mouse brain ( Espíndola et al, 2018 ; Damianich et al, 2021 ). To test SMaRT modulation of Tau in vivo , we used the htau mouse model ( Andorfer et al, 2003 ) which expresses a full length wild-type human MAPT transgene in an endogenous Mapt−/− background.…”

Does the Anti‐Tau Strategy in Progressive Supranuclear Palsy Need to Be Reconsidered? Yes

“…), preventing its aggregation, or enhancing its clearance, to a loss‐of‐function model where normal tau levels and function are restored. The importance of tau in its native configuration is highlighted by the fact that tau knockout models exhibit a neurological phenotype, including dopaminergic dysfunction 21 …”

“…The importance of tau in its native configuration is highlighted by the fact that tau knockout models exhibit a neurological phenotype, including dopaminergic dysfunction. 21 Protein aggregation is a physical problem pertaining to loss of solubility, with sequestration into insoluble cross-β fibers, also known as amyloids. Amyloid aggregation thus represents the end product of the soluble-to-insoluble phase transition of proteins, a functioning-to-nonfunctioning biological change.…”