Mutant huntingtin alters Tau phosphorylation and subcellular distribution

Abstract

Tau abnormalities play a central role in several neurodegenerative diseases, collectively known as tauopathies. In the present study, we examined whether mutant huntingtin (mHtt), which causes Huntington's disease (HD), modifies Tau phosphorylation and subcellular localization using cell and mouse HD models. Initially, we used novel bimolecular fluorescence complementation assays in live cells to evaluate Tau interactions with either wild type (25QHtt) or mutant huntingtin (103QHtt). While 25QHtt and Tau interacted at the level of the microtubule network, 103QHtt and Tau interacted and formed 'ring-like' inclusions localized in the vicinity of the microtubular organizing center (MTOC). Fluorescence recovery after photobleaching experiments also indicated that, whereas homomeric 103QHtt/103QHtt pairs rapidly re-entered into inclusions, heteromeric 103QHtt/Tau pairs remained excluded from the 'ring-like' inclusions. Interestingly, in vitro Tau relocalization was associated to Tau hyperphosphorylation. Consistent with this observation, we found strong Tau hyperphosphorylation in brain samples from two different mouse models of HD, R6/2 and 140CAG knock-in. This was associated with a significant reduction in the levels of Tau phosphatases (PP1, PP2A and PP2B), with no apparent involvement of major Tau kinases. Thus, the present study strongly suggests that expression of mHtt leads to Tau hyperphosphorylation, relocalization and sequestration through direct protein-protein interactions in inclusion-like compartments in the vicinity of the MTOC. Likewise, our data also suggest that Tau alterations may also contribute to HD pathogenesis.

Roles of tau protein in health and disease

“…R6/2 mice exhibit motor dysfunction and impaired learning and memory and intraneuronal inclusions of mutant huntingtin [99, 292]. Notably, increased tau phosphorylation is evident in the brains of R6/2 mice in parallel with reduced amounts of protein phosphatases [39, 174]. Increased tau phosphorylation has also been shown in HD, along with elevated GSK3 activity [268].…”

Amyloidogenesis of Tau protein

“…Moreover, Tau is hyperphosphorylated, prone to oligomerization and forms pathological deposits which co‐localize with the aggregates of mutant huntingtin in HD brains . Interestingly, expression of HD‐linked mutant of huntingtin has been demonstrated to induce Tau hyperphosphorylation and interaction of intracellular huntingtin inclusions with Tau may lead to the formation of huntingtin/Tau inclusions of ring‐like morphology …”

“…249 Interestingly, expression of HD-linked mutant of huntingtin has been demonstrated to induce Tau hyperphosphorylation and interaction of intracellular huntingtin inclusions with Tau may lead to the formation of huntingtin/Tau inclusions of ring-like morphology. 250 There are also numerous reports showing that pathological deposits of prion protein aggregates in TSEs may be accompanied by Tau pathology. Aggregates of hyperphosphorylated Tau have been detected in patients with familial and sporadic forms of TSEs, 152 as well as in animals experimentally infected with prion diseases.…”

Analyzing dendritic spine pathology in Alzheimer’s disease: problems and opportunities

“…LTP induction or pharmacological stimulation of synaptic activity increase translocation of tau to postsynapses [28]. Hyperphosphorylation of tau disrupts this localization pattern [22, 137, 222, 223]. Interestingly, there is also some evidence that phosphorylation of tau may be mediated by APP [137].…”