This is the 11th-article of a blog series aiming to introduce Zodiac, a comprehensive tool that reveals genetic interactions in cancer by big-data computation. An introduction of Zodiac is in the 1st article here.
Today I want to raise a bold question: Are genetic interactions between cancer and neurological disorders, such as Alzheimer disease (AD), similar? My current belief is that there are definitely similar genetic interactions between cancer and neurodisorders. In my previous two articles (here and here) I showed, as side notes, that some immune cancer biomarkers are related to genes with critical neurological functions. Today, I came across a Nature article published on Aug. 31, 2015, revealing a new physiological APP (this is the gene I will talk about) processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. This potentially has translational relevance for therapeutic strategies targeting APP processing in AD.
I learned from this article that APP is a critical gene for AD. So I looked up APP in Zodiac, which contains genome-wide gene-pair interactions in cancer. I did not expect to see much since Zodiac s is a database in cancer, not AD. Well, the top gene that co-express with APP is
PCDHB2 This gene is a member of the protocadherin beta gene cluster, one of three related gene clusters tandemly linked on chromosome five. The gene clusters demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The beta cluster contains 16 genes and 3 pseudogenes, each encoding 6 extracellular cadherin domains and a cytoplasmic tail that deviates from others in the cadherin superfamily. The extracellular domains interact in a homophilic manner to specify differential cell-cell connections. Unlike the alpha and gamma clusters, the transcripts from these genes are made up of only one large exon, not sharing common 3′ exons as expected. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins. Their specific functions are unknown but they most likely play a critical role in the establishment and function of specific cell-cell neural connections.
OK. I learned that the top gene “talks” with APP in cancer is PCDHB2, which is a member of a gene cluster related to cadherin. Cadherin is a critical protein that properly adheres cells together, so that they don’t wonder around in mature organs or tissues. Apparently, this is important physiologically. In cancer, cells do not properly bind to each other, and therefore become ill-shaped, like a tumor. Maybe when cells do not adhere to each other in brain, we get neural disorders, like Alzheimer?
Moving down the list, the second gene with top co-expression with APP is TMTC1. Humans know nothing about this gene.
The third gene is
FAT4 The protein encoded by this gene is a member of the protocadherin family. This gene may play a role in regulating planar cell polarity (PCP). Studies in mice suggest that loss of PCP signaling may cause cystic kidney disease, and mutations in this gene have been associated with Van Maldergem Syndrome 2.
It is a gene that regulate how cells shape in the space, which is called planar cell polarity. Surprisingly, FAT4 is a gene of the same protcadherin family as PCDHB2, the top gene above! This starts to give me goosebumps! Essentially the top two genes interact with APP are from the same gene family regulating spacing of cells. And neurodisorders like AD are affected by spacing of neural cells.
Moving on, the next gene is
GPRASP2 The protein encoded by this gene is a member of a family that regulates the activity of G protein-coupled receptors (GPCRs). The encoded protein has been shown to be capable of interacting with several GPCRs, including the M1 muscarinic acetylcholine receptor and the calcitonin receptor.
So it is a G protein-coupled receptor, or GPCR! What is a GPCR? It is a protein that has been awarded at least seven Nobel Prizes, including The 2012 Nobel Prize in Chemistry, awarded to Brian Kobilka and Robert Lefkowitz for their work that was “crucial for understanding how G protein–coupled receptors function.” It is apparently a very important protein and has been linked to at least the following nine physiological functions in human, among which 1, 2, 3, 4, 6, 7 are related to neural functions. Also, 5, 7 and 9 are related to cancer as well!
- The visual sense: The opsins use a photoisomerization reaction to translate electromagnetic radiation into cellular signals. Rhodopsin, for example, uses the conversion of 11-cis-retinal to all-trans-retinal for this purpose
- The gustatory sense (taste): GPCRs in taste cells mediate release of gustducin in response to bitter- and sweet-tasting substances.
- The sense of smell: Receptors of the olfactory epithelium bind odorants (olfactory receptors) and pheromones (vomeronasal receptors)
- Behavioral and mood regulation: Receptors in the mammalian brain bind several different neurotransmitters, including serotonin, dopamine, GABA, and glutamate
- Regulation of immune system activity and inflammation: Chemokine receptors bind ligands that mediate intercellular communication between cells of the immune system; receptors such as histamine receptors bind inflammatory mediators and engage target cell types in the inflammatory response. GPCRs are also involved in immune-modulation and directly involved in suppression of TLR-induced immune responses from T cells.
- Autonomic nervous system transmission: Both the sympathetic and parasympathetic nervous systems are regulated by GPCR pathways, responsible for control of many automatic functions of the body such as blood pressure, heart rate, and digestive processes
- Cell density sensing: A novel GPCR role in regulating cell density sensing.
- Homeostasis modulation (e.g., water balance).
- Involved in growth and metastasis of some types of tumors.
The next top gene co-expresses with APP in Zodiac is
NDN This intronless gene is located in the Prader-Willi syndrome deletion region. It is an imprinted gene and is expressed exclusively from the paternal allele. Studies in mouse suggest that the protein encoded by this gene may suppress growth in postmitotic neurons.
NDN is related to neurons.
At this point, I am convinced that Zodiac, albeit a database computed using cancer data, can reveal relationships of genes in neural disorders as well. This seems to suggest that disease-related genetic interactions in cancer and neural disorders might have overlaps.
To avoid making an overly long article, I decide to stop here. I start to suspect that many ill-functioned inter-cellular mechanisms in cancer might be also present in neural degenerate diseases such as Alzheimer. I wonder if any cancer therapies targeting these mechansims could be tested on neurodisorders, at least in cell lines and mice.