Human Disease Model Report: calcium-induced neurotoxicity, TRP-channel-related

General Information

Name

calcium-induced neurotoxicity, TRP-channel-related

FlyBase ID

FBhh0000723

Disease Ontology Term

neurodegenerative disease

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, trp^P365, 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).

(FlyBase Curators, 2013-)

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).

(FlyBase Curators, 2013-)

Cellular phenotype and pathology

The disruption of mitochondrial function appears to be a key aspect of calcium-induced neurotoxicity (FBrf0231847 and references cited therein).

(FlyBase Curators, 2013-)

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).

(FlyBase Curators, 2013-)

External links

Gene2Function (human gene): TRPC1 transient receptor potential cation channel subfamily C member 1
Gene2Function (human gene): TRPC4 transient receptor potential cation channel subfamily C member 4
Gene2Function (human gene): TRPC5 transient receptor potential cation channel subfamily C member 5
Gene Cards: TRPC1 gene
Gene Cards: TRPC4 gene
Gene Cards: TRPC5 gene
Gene Cards: TRPC1 transient receptor potential cation channel subfamily C member 1
Gene Cards: TRPC4 transient receptor potential cation channel subfamily C member 4
Gene Cards: TRPC5 transient receptor potential cation channel subfamily C member 5
MARRVEL (human gene): TRPC1 transient receptor potential cation channel subfamily C member 1
MARRVEL (human gene): TRPC4 transient receptor potential cation channel subfamily C member 4
MARRVEL (human gene): TRPC5 transient receptor potential cation channel subfamily C member 5
NCBI (Entrez) gene: TRPC1 transient receptor potential cation channel subfamily C member 1
NCBI (Entrez) gene: TRPC4 transient receptor potential cation channel subfamily C member 4
NCBI (Entrez) gene: TRPC5 transient receptor potential cation channel subfamily C member 5

Disease synonyms

Related Diseases

Related human health report(s)

mitochondrial disorders, VDAC-related

Ortholog Information

Human gene(s) in FlyBase

Other mammalian ortholog(s) used

D. melanogaster Gene Information (1)

Dmel\trp

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]

Molecular function (GO)

Cellular component (GO)

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

H. sapiens (Human)

Other Genes Used: Viral, Bacterial, Synthetic (0)

Summary of Physical Interactions (11 groups)

trp

protein-protein

Interacting group

Assay

References

trp

pull down, autoradiography, two hybrid, anti tag coimmunoprecipitation, anti tag western blot, coimmunoprecipitation, western blot

(Voolstra et al., 2017, Katz et al., 2013, Xu et al., 1997)

trp - Cam

pull down, molecular weight estimation by staining, static light scattering, predetermined participant, cosedimentation, confirmation by molecular weight, x-ray crystallography, isothermal titration calorimetry, western blot, nuclear magnetic resonance, molecular sieving

(Chen et al., 2021, Sun et al., 2018, Chevesich et al., 1997)

trp - Gαq

anti bait coimmunoprecipitation, western blot

(Bahner et al., 2000)

trp - inaC

pull down, Identification by mass spectrometry, enzymatic study, autoradiography, peptide massfingerprinting, western blot, anti bait coimmunoprecipitation, molecular weight estimation by staining

(Chen and Montell, 2020, Peng et al., 2008, Popescu et al., 2006, Bahner et al., 2000, Liu et al., 2000)

trp - inaD

pull down, autoradiography, western blot, anti bait coimmunoprecipitation, far western blotting, nuclear magnetic resonance, Identification by mass spectrometry, predetermined participant, anti tag coimmunoprecipitation, cosedimentation, fluorescence polarization spectroscopy, molecular sieving, molecular weight estimation by staining

(Chen and Montell, 2020, Voolstra et al., 2017, Ye et al., 2016, Chen et al., 2015, Katz et al., 2013, Liu et al., 2011, Peng et al., 2008, Bahner et al., 2000, Li and Montell, 2000, Wes et al., 1999, Tsunoda et al., 1997, Shieh and Zhu, 1996)

trp - inaF-B

anti bait coimmunoprecipitation, anti tag western blot, anti tag coimmunoprecipitation, western blot, pull down, Identification by mass spectrometry

(Chen and Montell, 2020, Cheng and Nash, 2007)

trp - inaF-C

anti tag coimmunoprecipitation, western blot, pull down, Identification by mass spectrometry, anti tag western blot

(Chen and Montell, 2020)

trp - ninaE

anti bait coimmunoprecipitation, western blot

(Chevesich et al., 1997)

trp - norpA

anti bait coimmunoprecipitation, western blot, molecular weight estimation by staining, pull down, Identification by mass spectrometry

(Chen and Montell, 2020, Peng et al., 2008, Bahner et al., 2000, Chevesich et al., 1997)

trp - trpl

anti bait coimmunoprecipitation, western blot, two hybrid, coimmunoprecipitation, anti tag coimmunoprecipitation, anti tag western blot, pull down, autoradiography

(Xu et al., 1997)

trp - Xport-A

western blot, anti bait coimmunoprecipitation

(Rosenbaum et al., 2011)

Alleles Reported to Model Human Disease (Disease Ontology) (2 alleles)

trp

Models Based on Experimental Evidence ( 2 )

Allele

Disease

Evidence

References

trp¹