FTDP-17 Tau Mutations Induce Distinct Effects on Aggregation and Microtubule Interactions

Abstract

FTDP-17 mutations in the tau gene lead to early-onset frontotemporal dementias characterized by the pathological aggregation of the microtubule-associated protein tau. Tau aggregation is closely correlated with the progression and severity of localized atrophy of certain regions in the brain. These mutations are primarily located in or near the microtubule-binding repeat regions of tau and can have vastly different effects on the protein. Some mutations have been linked to effects such as increased aggregation, hyperphosphorylation, defects in mRNA splicing, and decreased interaction with microtubules. Given the differential effects of the mutations it may not be surprising that the pathology associated with FTDP-17 can vary widely as well. Despite this variety, several of the mutations are commonly used interchangeably as aggregation inducers for in vitro and in vivo models of tauopathies. We generated recombinant forms of 12 FTDP-17 mutations chosen for their predicted effects on the charge, hydrophobicity, and secondary structure of the protein. We then examined the effects that the mutations had on the properties of in vitro aggregation of the protein and its ability to stabilize microtubule assembly. The group of mutations induced very different effects on the total amount of aggregation, the kinetics of aggregation, and filament morphology. Several of the mutations inhibited the microtubule-stabilization ability of tau while others had very little effect compared to wild-type tau. These results indicate that the mechanisms of disease progression may differ among FTDP-17 mutations and that the effects of the varying mutations may not be equal in all model systems.

Interactions between Microtubule-Associated Protein Tau (MAPT) and Small Molecules

“…Indeed, it is known that phosphorylation and mutation play a key role in aggregation kinetics (Chang et al 2011; Combs and Gamblin 2012), suggesting that some molecules may be more or less effective at preventing their aggregation. We suggest that future efforts might better integrate knowledge of disease-associated variations to focus small molecule discovery campaigns.…”

“…NMR is a powerful way to study tau monomers in solution (Mukrasch et al 2009) and electron microscopy (EM) has begun to show the structures of fibrils (Combs and Gamblin 2012), yet we still have little understanding of how tau prions or oligomers form or what they look like. Because of the heterogeneity of tau aggregates, classical structural methods have difficulty uncovering the nature of these structures.…”

Expression and purification of tau protein and its frontotemporal dementia variants using a cleavable histidine tag

“…To this end, recombinant tau has been used extensively to study the molecular, biochemical and cellular aspects of the protein's functions, including (i) binding to MTs in physiological and pathological conditions (ii) tau-tau interactions leading to their aggregation into toxic paired helical filaments (PHFs) that are similar to those isolated from the brains of Alzheimer's disease patients, and (iii) the transcellular spread of this toxicity in affected organisms [4], [5], [6], [7], [8], [9], [10]. The binding of tau to MTs is disrupted in disease and also by the presence of specific FTPD-17 mutations some of which can enhance the protein's aggregation into PHFs [6], [9], [11], [12]. Furthermore, truncated tau constructs such as the repeat domains are aggregation - prone and demonstrate enhanced aggregation kinetics compared to the full-length isoforms [13], [14].…”

In vivo axonal transport deficits in a mouse model of fronto-temporal dementia

“…The tau mutations in FTDP-17 have been linked to two major pathological outcomes (Combs and Gamblin, 2012). The first of these is disruption in alternative splicing that leads to a higher ratio of 4R tau rather than 3R tau.…”