Year: 2017
Type: article
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 reflect the splicing in or out of exons 2, 3, and 10 in the MAPT gene on chromosome 17. There are six isoforms of tau, three with exon 10 spliced in (2-3-10; 2-10; 3-10) giving rise to tau with four microtubule-binding domains, and three with exon 10 spliced out (2-3; 2; 3) giving rise to tau with three microtubule-binding domains. The findings from this study have several important implications for the FTLD field. First, the authors have demonstrated that the distinction in pathology between sporadic and genetic FTLD is artificial. They therefore argue that the term FTDP-17 should be eliminated once and for all, with cases of FTLD with MAPT mutations considered familial forms of FTLD-tau. And why not? The investigators argue that we could learn a great deal about the sporadic forms of FTLD-tau by modelling their genetic counterparts. In fact, in Alzheimer’s disease, a wealth of knowledge about the mechanisms underlying amyloid-β and neurofibrillary tau deposition and function has been obtained through the study of genetic variants of the disease. Similarly, in other neurodegenerative disorders such as Parkinson’s disease and amyotrophic lateral sclerosis, genetic forms of the disease—including transgenic animal models for α-synuclein (Abeliovich et al., 2000) and TDP-43 (Wegorzewska et al., 2009)—have allowed for a better understanding of the cellular mechanism underlying the sporadic forms. Furthermore, it is already the case that genetic forms of FTLD, such as that caused by mutations in C9orf72, have improved our understanding of sporadic FTLD-TDP, and even provided potential therapeutic options (Kramer et al., 2016). One reason for the lag in development of a similar construct for MAPT mutations has been the heterogeneous pathologies associated with the archaic entity FTDP-17, and the lack of a vision to try to map these pathologies onto the subtypes of FTLD-tau in a systematic way. Another key finding that can be gleaned from this study is the importance of the tau isoform distinction in both sporadic and familial FTLD-tau, as the literature summarized by Forrest et al. revealed only rare instances, requiring confirmation, of an identical MAPT mutation being associated with different FTLD-tau isoform pathologies. In fact, there was evidence to suggest that mutations in specific exons and introns may be associated with only one isoform type. On the other hand there were many instances where the same mutation was associated with a different 4R FTLD-tau pathology. Forrest et al. argue that this is evidence that there are additional genetic factors at play. Alternatively, in cases where different mutations yield the same FTLD-tau pathology, the tau may have varying functional properties. One limitation of the study is the relatively small number of cases with a MAPT mutation and FTLD-tau pathology that were analysed. As a result, a number of mutations were not represented in the study. To overcome this limitation, Forrest et al. performed a systematic analysis of the published literature on other mutations. This is a welcome addition to the study as it extends and further validates the concept that there are no pathological differences between genetic and sporadic forms of FTLD-tau. Unfortunately, as the authors pointed out, some of the cases in the literature were not well characterized pathologically, and therefore the classification of such cases into one of the FTLD-tau variants must be regarded as less certain, especially those cases considered to have familial Pick’s disease, yet reported to show mixed 3R+4R tau. Further work is needed to assess these mutations, and others not discussed, such as the V337M mutation, which produces tau pathology identical to that of Alzheimer’s disease (Spillantini et al., 1996). Regardless, the idea of entombing FTDP-17 and revising pathological classification of the FTLD-tau group as outlined by this study is significant, and is likely to result in better understanding of the cellular mechanisms underlying sporadic FTLD-tau.
Source: Brain
DOI: 10.1093/brain/awx367
Author: Keith A Josephs
Institution: Mayo Clinic
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2792029754