MAPT mutations, tauopathy, and mechanisms of neurodegeneration

Abstract

In multiple neurodegenerative diseases, including Alzheimer's disease (AD), a prominent pathological feature is the aberrant aggregation and inclusion formation of the microtubule-associated protein tau. Because of the pathological association, these disorders are often referred to as tauopathies. Mutations in the MAPT gene that encodes tau can cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), providing the clearest evidence that tauopathy plays a causal role in neurodegeneration. However, large gaps in our knowledge remain regarding how various FTDP-17-linked tau mutations promote tau aggregation and neurodegeneration, and, more generally, how the tauopathy is linked to neurodegeneration. Herein, we review what is known about how FTDP-17-linked pathogenic MAPT mutations cause disease, with a major focus on the prion-like properties of wild-type and mutant tau proteins. The hypothesized mechanisms by which mutations in the MAPT gene promote tauopathy are quite varied and may not provide definitive insights into how tauopathy arises in the absence of mutation. Further, differences in the ability of tau and mutant tau proteins to support prion-like propagation in various model systems raise questions about the generalizability of this mechanism in various tauopathies. Notably, understanding the mechanisms of tauopathy induction and spread and tau-induced neurodegeneration has important implications for tau-targeting therapeutics.

Figure 1.. The longest tau isoform found in the human brain, with its corresponding mRNA and known pathogenic missense and deletion mutations.

The MAPT mRNA resulting in 2N4R tau is shown with an embedded number corresponding to the originating exon. Exon 1 contains both untranslated 5’ region and the start of the protein. Exons 2 and 3 are present in this isoform as N1 and N2 inserts; however, in the 1N and 0N isoforms of tau, exon 2 or neither exon 2 or 3 are translated, respectively. MT-binding repeat 2, or R2, is present in this isoform; however, in 3R tau, exon 10 is alternatively spliced and this region is not present in the protein. The different colors serve to highlight regions of the protein that are alternatively spliced as well as the MT-binding domain. The N-terminus, proline-rich, MT-binding and C-terminal regions are indicated above. Below the protein, known pathogenic missense mutations are indicated. Many of these mutations reside in the MT-binding region, and as such the specific amino acid sequence of this area is shown. The PHF6* and PHF6 motifs that are important for tau aggregation are also indicated.

Figure 2.. Schematic of the RNA stem loop present at the end of exon 10 and the beginning of intron 10.

Known pathogenic exonic (both missense and silent) and intronic mutations with their corresponding amino acid changes or deletions, when applicable, are shown. The boundary between exon 10 and intron 10 is indicated by the partition at the top left, and also by the use of lower case letters for intron 10. Mutations in this region that have been shown to increase exon 10 inclusion are indicated in red, while those that have been shown to decrease exon 10 inclusion are indicated in green. Mutations that have not been shown to affect splicing are represented in black.