A number of inherited neurodegenerative disorders are associated with aggregation of tau protein in the brain. This report describes fly disease models using the human MAPT gene (microtubule-associated protein tau) and the orthologous Drosophila tau gene. For the fly gene, overexpression UAS-tau alleles, RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated; an amorphic Dmel\tau allele has been created via gene targeting and recombination.
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 frontotemporal dementia (FTD); 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 G272V (G589V), P301L (P618L), V337M (V654M), S352L (S669L) and R406W (R723W) have been introduced into flies. These variants are implicated in frontotemporal dementia (FTDP-17; FBhh0000111, OMIM:600274); the variant P301L (P618L) is also implicated in progressive supranuclear palsy 1 (PSNP1; FBhh0000113, OMIM:601104). Additional variant(s) implicated in human disease tested (as transgenic human gene, MAPT): the variant forms R5L, S320F, and G389R have been introduced into flies; R5L is implicated in PSNP1; S320F and G389R are postulated to be pathogenic.
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.
See also allele reports for two marker constructs that incorporate Btau\MAPT (bovine tau) sequences, Ecol\lacZUAS.O.Tag:MT(btau) and Avic\GFPUAS.S65T.I167T.Tag:MT(btau).
[updated Feb. 2018 by FlyBase; FBrf0222196]
Tauopathies are a group of diseases which includes frontotemporal dementia (OMIM:600274), progressive supranuclear palsy (OMIM:601104), and Pick disease (OMIM:172700) (from http://www.mayo.edu/research/labs/neurodegenerative-diseases/targeting-tau-treatment-tauopathies). These neurodegenerative diseases are characterized by the pathological aggregation of tau protein in the brain. Symptoms typically observed include changes in personality and behavior, speech and language abnormalities, problems with movement, and eventual cognitive decline (Genetics Home Reference; MAPT gene; 2016.01.11).
Mutations in the human gene MAPT (microtubule-associated protein tau) are implicated in multiple diseases classified as tauopathies. [from OMIM:157140; 2016.01.11]
Microtubule-associated protein tau (MAPT) is one of a large number of proteins in different cell types that coassemble with tubulin in microtubules; MAPT appears to be enriched in axons. [from OMIM:157140; 2016.01.08]
The MAPT protein promotes microtubule assembly and stability, and might be involved in the establishment and maintenance of neuronal polarity. The human MAPT gene undergoes regulated alterative splicing, producing several different protein isoforms. [UniProt:P10636; 2016.01.11]
The accumulation of hyperphosphorylated tau causes the formation of neurofibrillary tangles, a pathological characteristic of tauopathies. [from http://www.mayo.edu/research/labs/neurodegenerative-diseases/targeting-tau-treatment-tauopathies]
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.
