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General Information
Name
calcium-induced neurotoxicity, TRP-channel-related
FlyBase ID
FBhh0000723
Disease Ontology Term
Parent Disease
OMIM
Overview

Transient receptor potential (TRP) cation channels play key roles in maintaining intracellular calcium homeostasis. High levels of intracellular calcium are cytotoxic; the dysregulation of calcium homeostasis is involved in the pathogenesis of a number of neurodegenerative diseases. There are many genes encoding TRP channels in both human (28 described, see link below) and Drosophila (13 described, see link below). The Drosophila TRP channel gene trp has been used to model calcium-induced neurotoxicity in flies. Classical loss-of-function alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\trp.

Dmel\trp is most closely related to the human genes TRPC1, TRPC4, and TRPC5. None of these human genes has been introduced into flies.

Dmel\trp is expressed primarily in the adult eye and contributes to the electrical response to light in photoreceptors. A constitutively active form of trp results in increased levels of cellular calcium and retinal degeneration; photoreceptor cells contain morphologically abnormal mitochondria. This system has been used to investigate the mechanisms by which elevated cellular calcium causes cell death. The retinal degeneration phenotype is ameliorated by genetic activation of autophagy, including overexpression of genes implicated in Parkinson disease (PARK 2, FBhh0000008; PARK6, FBhh0000009). Many physical and genetic interactions of Dmel\trp have been described; see below and in the trp gene report.

A constitutively active form of Dmel\trp, trpP365, has been used extensively. There are 4 missense mutations associated with this allele: P500T, H531N, F550I, S867F. Of these sites, F550 is located within the beginning of the predicted S5 transmembrane domain and is highly conserved in TRP channels. A mutation in mouse in the TRPML gene and mutations in the human TRPV4 gene implicated in brachyolmia map within the same conserved region (Myer et al., 2008; pubmed:18955590).

See also the human disease model report 'mitochondrial disorders, VDAC-related' (FBhh0000722).

[updated Feb. 2018 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: calcium-induced neurotoxicity, TRP-channel-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype
The dysregulation of calcium homeostasis is involved in the pathogenesis of various neurodegenerative diseases, including rapid forms of neurodegeneration associated with ischemia or brain injury, as well as slowly progressing neurodegenerative diseases such as Alzheimer disease, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis (FBrf0231847 and references cited therein).
Genetics
There are many genes encoding TRP channels in both human (see https://www.genenames.org/cgi-bin/genefamilies/set/249) and Drosophila (see http://flybase.org/reports/FBgg0000358.html).
Cellular phenotype and pathology
The disruption of mitochondrial function appears to be a key aspect of calcium-induced neurotoxicity (FBrf0231847 and references cited therein).
Molecular information
TRP channels play prominent roles in the regulation of the intracellular calcium level in both excitable and nonexcitable cells. TRP channels are classified into six subfamilies: the TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), and the TRPA (ankyrin) groups (Gees et al., 2010; pubmed:20861159).
Disease synonyms
Ortholog Information
Human gene(s) in FlyBase
    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (1)
      Gene Snapshot
      transient receptor potential (trp) encodes a non-selective plasma membrane cation channel with high Ca[2+] permeability. It is highly eye-enriched and contributes to the electrical response to light in photoreceptors. [Date last reviewed: 2019-03-14]
      Gene Groups / Pathways
      Comments on ortholog(s)
      Moderate-scoring ortholog of human TRPC1, TRPC4, and TRPC5 (many homologous genes in both species); Dmel\trp shares 36-40% identity and 54-58% 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 (9 groups)
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, western blot
      isothermal titration calorimetry, predetermined participant, pull down, western blot, static light scattering
      anti bait coimmunoprecipitation, western blot
      pull down, western blot, enzymatic study, autoradiography, anti bait coimmunoprecipitation, molecular weight estimation by staining, peptide massfingerprinting
      anti bait coimmunoprecipitation, molecular weight estimation by staining, western blot, pull down, far western blotting, autoradiography, nuclear magnetic resonance, cosedimentation, anti tag coimmunoprecipitation, molecular sieving, fluorescence polarization spectroscopy, predetermined participant
      anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, anti tag western blot
      anti bait coimmunoprecipitation, western blot
      anti bait coimmunoprecipitation, molecular weight estimation by staining, western blot, pull down
      western blot, anti bait coimmunoprecipitation
      Alleles Reported to Model Human Disease (Disease Ontology) (1 alleles)
      Models Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 1 )
      Allele
      Disease
      Interaction
      References
      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
      loss of function allele
      ethyl methanesulfonate
      loss of function allele
      ethyl methanesulfonate
      References (9)