Rest in peace FTDP-17

Abstract

This scientific commentary refers to ‘Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies’ by Forrest et al. (doi:10.1093/brain/awx328). The frontotemporal lobar degenerations (FTLDs) are a group of neuropathologically-defined entities characterized by the presence or absence of specific, abnormally deposited, proteins. Three main proteins account for the vast majority of the FTLDs, namely the microtubule-associated protein, tau (MAPT), the TAR DNA binding protein of 43 kDa (TDP-43, encoded by TARDBP), and the ‘fused in sarcoma’ protein (FUS). In the majority of instances, the FTLDs are therefore pathologically classified as FTLD-tau, FTLD-TDP or FTLD-FUS (Mackenzie et al., 2010), with any remaining pathologies being relatively rare. Subclassifications of these three categories are based on additional molecular properties of the protein, e.g. isoform, distinct morphological characteristics, and other histopathological features. As a result, there are subtypes of FTLD-tau including progressive supranuclear palsy, corticobasal degeneration, Pick’s disease and globular glial tauopathies; subtypes of FTLD-TDP including FTLD-TDP type A, type B, type C and type D, and subtypes of FTLD-FUS including neuronal intranuclear inclusion disease, basophilic inclusion body disease and atypical FTLD with ubiquitinated inclusions (Mackenzie et al., 2010). These pathological diagnoses, however, are specific to sporadic FTLD cases, i.e. cases without an identifiable genetic mutation. Within the FTLD field, sporadic and genetic FTLD tend to be considered as separate entities, although there have been cases with identifiable genetic mutations showing FTLD pathology indistinguishable from cases without a mutation. This has been particularly problematic for mutations in the MAPT gene on chromosome 17. The term ‘frontotemporal degeneration with parkinsonism linked to chromosome 17’ (FTDP-17) was coined almost two decades ago to account for cases of FTLD associated with mutations in MAPT (Foster et al., 1997). However, the term later became problematic when another mutation, also on chromosome 17, was identified in the progranulin gene (GRN) and shown to be associated with FTLD (Baker et al., 2006; Cruts et al., 2006), and when cases of FTLD with MAPT mutations but without parkinsonism were identified. Nevertheless, the term FTDP-17 hobbled on for almost 20 years as a distinct entity, separate from FTLD-tau. In this issue of Brain, Forrest and co-workers provide evidence that cases of FTLD associated with distinct mutations in MAPT are no different pathologically from the sporadic FTLD-tau subtypes, and champion the notion that FTLD caused by MAPT mutations should be considered a familial form of sporadic FTLD-tau (Forrest et al., 2018). The MAPT gene consists of 16 exons. Alternative splicing of exons 2, 3 and 10 yields six different tau isoforms; three isoforms with three microtubule-binding domains (3R tau) and three isoforms with four microtubule-binding domains (4R tau). Progressive supranuclear palsy, corticobasal degeneration and globular glial tauopathies are examples of FTLD-tau associated with 4R tau isoforms, while Pick’s disease is associated with 3R tau (Dickson et al., 2011). An example of a mixed 3R+4R tau disease is Alzheimer’s disease. From a large cohort of almost 200 FTLD cases, Forrest et al. analysed the pathological features of 10 cases with five different mutations in the MAPT gene (K257T, S305S, P301L, IVS10+16, R406W) in eight independent families. They assessed the molecular and morphological characteristics as well as the burden of intra and extracellular tau deposition in the 10 cases, and compared the histological features to sporadic cases of FTLD-tau, including progressive supranuclear palsy, corticobasal degeneration, globular glial tauopathies, and Pick’s disease (Forrest et al., 2018). The investigators found that the hallmark pathological features of cases with sporadic Pick’s disease also occurred in the case with the K257T mutation. Furthermore, the hallmark neuropathological features of corticobasal degeneration were identified in five cases with the S305S (n = 2), R406W and IVS10+16 (n = 2) mutations, while the hallmark neuropathological features of progressive supranuclear palsy were observed in a case with the S305S mutation. The remaining three cases with a P301L or IVS10+16 (n = 2) mutation showed classic features of a globular glial tauopathy (Fig. 1). There were few clinical differences between genetic FTLD-tau and sporadic FTLD-tau cases when stratified by pathological subtype, including disease duration, although those with genetic FTLD-tau had a younger age at onset. Schematic representing sporadic and genetic forms of frontotemporal lobar degeneration with tau (FTLD-tau). The arrows show how mutations in MAPT map onto the sporadic pathologies, as described by Forrest et al. (2018). Glossary Tau isoform: Different forms of tau that refl