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 the 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 raises questions about the generalizability of this mechanism in various tauopathies. Notably, understanding the mechanisms of tauopathy induction and spread and tau-induced neurodegeneration have important implications for tau-targeting therapeutics.

The C291R Tau Variant Forms Different Types of Protofibrils

“…In vitro biochemical studies provide critical molecular insights into potential disease-causing mechanisms of MAPT mutations identified in humans affected by specific tauopathies including effects on tau aggregation, phosphorylation, and microtubulebinding (Ghetti et al, 2015;Strang et al, 2019). However, little is known about MAPT mutations discovered more recently.…”

Reference SVA insertion polymorphisms are associated with dopaminergic degeneration in Parkinson’s Disease and differential gene expression in the PPMI cohort

“…H1 is associated with increased risk of developing PD in multiple studies (22)(23)(24). This region encompasses several genes and includes MAPT in which mutations can cause the neurodegenerative diseases frontotemporal dementia with parkinsonism and progressive supranuclear palsy (25,26).…”

Xenobiotics, Trace Metals and Genetics in the Pathogenesis of Tauopathies

“…Nevertheless, it is known that mutations in the tau gene may affect microtubule construction, resulting in increased tau self-aggregation. A recent review by Strang et al [49] discusses the impact of MAPT mutations on tauopathies and neurodegeneration. Since the initial discovery in 1998 [50], several families with MAPT mutations and progressive phenotypes similar to PSP have been identified [51].…”