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General Information
Name
frontotemporal dementia with parkinsonism 17
FlyBase ID
FBhh0000111
Disease Ontology Term
Parent Disease
OMIM
Overview

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 OMIM: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]

Disease Summary Information
Parent Disease Summary: frontotemporal dementia
Symptoms and phenotype

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 OMIM:600274; 2016.01.11]

Specific Disease Summary: frontotemporal dementia with parkinsonism 17
OMIM report
Human gene(s) implicated
Symptoms and phenotype

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)

Genetics

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).

Cellular phenotype and pathology

Neuropathological findings include frontotemporal atrophy and aggregation of tau protein. [from OMIM:600274; 2019.08.14]

Molecular information
External links
Disease synonyms
FTD
frontotemporal dementia with parkinsonism-1
FTDP17
Pick complex
Pick disease
frontotemporal lobar degeneration with tau inclusions
multiple system tauopathy with presenile dementia
Wilhemsen-Lynch disease
FTDP-17
frontotemporal dementia with parkinsonism linked to chromosome 17
frontotemporal dementia
dementia, frontotemporal, with parkinsonism
FTLD-tau
frontotemporal dementia, MAPT-related
frontotemporal lobar degeneration, tau
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

Many to one: 3 human to 1 Drosophila. Three human genes, MAPT, MAP2 and MAP4, are orthologous to the fly gene Dmel\tau.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    In progress.Contributions welcome.
    Molecular function (GO)
    Gene Groups / Pathways
      Comments on ortholog(s)

      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.

      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      Synthetic Gene(s) Used (0)
      Summary of Physical Interactions (4 groups)
      protein-protein
      Interacting group
      Assay
      References
      coimmunoprecipitation, western blot, affinity technology
      coimmunoprecipitation, western blot, affinity technology
      anti bait coimmunoprecipitation, anti tag western blot
      RNA-RNA
      Interacting group
      Assay
      References
      western blot, quantitative reverse transcription pcr
      Alleles Reported to Model Human Disease (Disease Ontology) (65 alleles)
      Models Based on Experimental Evidence ( 55 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 24 )
      Allele
      Disease
      Interaction
      References
      model of  tauopathy
      is ameliorated by Atg1Δ3D
      is ameliorated by S6kUAS.cUa
      is ameliorated by arm1
      is ameliorated by sgg1
      is exacerbated by panUAS.cWa
      is ameliorated by arm4
      is ameliorated by Vap33Δ448
      is exacerbated by Psa06226
      is ameliorated by POLDIP2EY08866
      is exacerbated by spinΔ2b
      model of  tauopathy
      is exacerbated by f+t13
      is ameliorated by GelUAS.cDa
      is ameliorated by Opa1s3475
      is ameliorated by MarfJF01650
      is exacerbated by MarfUAS.cDa
      is ameliorated by Drp1UAS.cDb
      is exacerbated by WASpUAS.cBa
      is exacerbated by sqhAX3
      is exacerbated by Drp1GD10456
      is exacerbated by zip1
      is ameliorated by JHDM2HMJ22328
      is ameliorated by Kdm2KK101783
      is ameliorated by Kdm4AGD9133
      is ameliorated by Kdm4BKK102089
      is exacerbated by Klc8ex94
      is exacerbated by AmphEY09339
      is exacerbated by ClcDG23206
      is exacerbated by Chc1
      is exacerbated by Chc4
      is ameliorated by Rab26UAS.YFP
      is exacerbated by Rab26GD9927
      is exacerbated by AmphGD1311
      is exacerbated by SytβDG10711
      is exacerbated by p535A-1-4
      is exacerbated by p5311-1B-1
      is exacerbated by SytβJF02593
      is exacerbated by LerpGD306
      is exacerbated by gGD7158
      is exacerbated by SppGD786
      is exacerbated by DabGD4886
      is exacerbated by krzGD8470
      is exacerbated by ttvGD1993
      is ameliorated by hepGD1461
      is ameliorated by TetGD9718
      is exacerbated by Lkb1UAS.cWa
      is exacerbated by cathD1
      model of  tauopathy
      is ameliorated by HDAC6KO
      is ameliorated by CalpB4062
      is ameliorated by twsUAS.cBa
      is exacerbated by hop2
      is ameliorated by CaMKIIGD9506
      is exacerbated by CaMKIIUAS.cKa
      is exacerbated by Klc8ex94
      is ameliorated by MESR4EP386
      is ameliorated by gEP514
      is ameliorated by mubEP3108
      is ameliorated by svrEP356
      model of  tauopathy
      is ameliorated by HDAC6KO
      is exacerbated by Diap1SL
      is ameliorated by αTub84BK40Q
      is ameliorated by αTub84BK40R
      is ameliorated by MycJF01761
      is exacerbated by SmBHM05097
      is exacerbated by SmBKK102021
      is exacerbated by SmD2GD7741
      is exacerbated by SmD2HMC03839
      is exacerbated by SmEGD13663
      is exacerbated by SmEHMS00074
      is exacerbated by snfJ210
      is ameliorated by Act5CG0010
      is exacerbated by Act5CUAS.GFP
      Models Based on Experimental Evidence ( 4 )
      Modifiers Based on Experimental Evidence ( 4 )
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Selected mammalian transgenes
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      amorphic allele - molecular evidence
      ends-out gene targeting
      References (18)