Because many of these mutations present neuropathologically in a manner consistent with different sporadic tauopathies such as PSP, CBD, PiD( 13– 15), there have recently been calls to characterize tauopathy caused by certain mutations as familial versions of these specific diseases( 16). These MAPT mutations can cause variable cognitive, behavioral and motor deficits, with an average age of onset of 49 years and duration of disease of 8.5 years( 12).Īs of 2018, over 50 different pathogenic MAPT missense, silent and intronic mutations have been reported ( Figs. Disease pathology for individuals with FTDP-17t are characterized by the presence of filamentous tau inclusions throughout the frontal and temporal lobes in neurons and sometimes in glia, accompanied by atrophy in these regions, as well as ventricular dilation( 11).

In 1998, autosomal dominant mutations in the MAPT gene that encodes tau were found to cause some forms of FTDP-17( 8– 10), now referred to as FTDP-17t, proving that tau dysfunction is sufficient for widespread central nervous system neurodegeneration. First discovered as a MT-associated protein in 1975( 6), tau was later found to be the principal component of neurofibrillary tangles (NFTs), which are hyperphosphorylated proteinaceous inclusions found in AD and other tauopathies( 7). Tauopathies refer to a wide range of phenotypically diverse diseases characterized by the aberrant aggregation of tau in neurons and/or glia, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease (PiD), chronic traumatic encephalopathy (CTE), and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17)( 5). One of tau’s primary functions is to bind to and promote the assembly and stability of MTs this binding activity that can be negatively regulated by phosphorylation at select sites( 1, 4). Higher molecular mass isoforms generated through alternative splicing, often termed “big tau,” are expressed primarily in the peripheral nervous system, but are sometimes also observed in spinal cord and skeletal muscle, when exon 4a and exon 6 are translated, respectively( 1– 3). The microtubule (MT) associated protein tau (MAPT) is an intrinsically disordered protein expressed at its highest levels in neurons throughout the central nervous system. Notably, understanding the mechanisms of tauopathy induction and spread and tau-induced neurodegeneration have important implications for tau-targeting therapeutics. 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. 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. 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. 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.

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. Because of the pathological association, these disorders are often referred to as tauopathies.

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.

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