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FB2025_05
,
released December 11, 2025
Frontotemporal dementia with parkinsonism 17 (FTDP-17) encompasses a number of inherited neurodegenerative disorders with overlapping phenotypes associated with the MAPT (microtubule-associated protein tau) gene on chromosome 17. FTDP-17 exhibits autosomal dominant inheritance. Additional experiments done in flies using the human MAPT gene and the orthologous Drosophila tau gene are described in the report titled 'tauopathies, MAPT-related' (FBhh0000101).
Many different UAS constructs of the human Hsap\MAPT gene have been introduced into flies, including wild-type MAPT and genes carrying mutational lesions implicated in FTDP-17; constructs expressed specifically in the eye have also been generated. Heterologous rescue (functional complementation) is observed for some aspects of the loss-of-function phenotypes described for an RNAi construct that targets Dmel\tau. Phenotypic assays using the human gene have allowed characterization of genetic interactions with candidate fly genes and transgenic human genes.
Variant(s) implicated in human disease tested (as transgenic human gene, MAPT): the variant forms R5L, G589V (G272V), P618L (P301L), V654M (V337M), S637F (S320F), S669L (S352L), G706R (G389R), R723W (R406W) have been introduced into flies. Some researchers categorize all pathologies associated with variants of MAPT as one disease spectrum. However, others indicate specific variants as implicated in progressive supranuclear palsy 1 (FBhh0000113) or in Pick disease (Pick disease of brain, FBhh0000112), among others (see MIM:157140).
RNAi-effected reduction in levels of Dmel\tau using a general GAL4 driver results in larval/pupal lethality; reduction specifically in the developing eye causes progressive neurodegeneration. Genetic and physical interactions of Dmel\tau have been described; see below and in the tau gene report.
[updated Aug. 2019 by FlyBase; FBrf0222196]
Frontotemporal dementia (FTD) refers to a clinical manifestation of the pathologic finding of frontotemporal lobar degeneration. Effects upon speech are commonly observed; symptoms include loss of volition, executive dysfunction, loss of abstract thought, and decreased speech output, specific loss of comprehension of language and impaired facial and object recognition. There is relative preservation of memory, at least in the early stages. [from MIM:600274; 2016.01.11]
Frontotemporal dementia associated with MAPT mutations is a disorder that affects multiple domains including behavior, language, memory and motor function. It often begins with psychiatric symptoms and can mimic Pick disease, primary progressive aphasia, Alzheimer disease (AD), progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD). (Ghetti et al., 2015; pubmed:25556536)
FTDP-17 is caused by heterozygous mutation in the MAPT gene.
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 (Josephs, 2018; pubmed:29390124).
Neuropathological findings include frontotemporal atrophy and aggregation of tau protein. [from MIM:600274; 2019.08.14]
Many to one: 3 human to 1 Drosophila. Three human genes, MAPT, MAP2 and MAP4, are orthologous to the fly gene Dmel\tau.
Ortholog of human MAPT (reciprocal best hit), MAP2, and MAP4 (1 Drosophila to 3 human). The 3 human proteins are much longer; Dmel\tau aligns to the tubulin-binding domains at the carboxy termini. Within the aligned region, Dmel\tau shares shares 28-33% identity and 44-46% similarity with the 3 human genes.