On page 2043, of the Santagata, et al paper, the authors mention Arabidopsis. What is the function of tubby proteins in Arabidopsis and other plants. Rachael, have you come across this in your research on homology?
In the paper it mentioned that there is a family of "tubby" genes found in humans; Tubby, TULP 1, 2, and 3. Due to the homology of the genes, it is pretty likely that the genes could have similar mechanisms. It was stated that a mutation (or deletion of the tubby gene) causes an obese phenotype but a mutation in the TULP1 gene has been linked to retinitis pigmentosa type 14. I found it pretty odd that a mutation in two similar genes could cause extremely different phenotypes. Do you think there is any correlation obesity and retinitis pigmentosa?
In both the article and the reviews they mention that the TUB protein normally originates in the plasma membrane, but when it is over expressed the TUB protein migrates to the nucleus. They showed this by gel electrophoresis where the protein migrates from the plasma membrane through the cytoplasm, briefly, and into the nucleus, where there is a strong expression. Why does the TUB protein choose to go to the nucleus upon over-expression? Is there a purpose for doing this?
In the review "Tubby Proteins: The Plot Thickens", there is description of the phenotype of a null mutation of the TUB gene. In addition to obesity and insulin resistance, retinal and cochlear degeneration are also present in the double mutant. I had not heard of these symptoms being associated with obesity in humans. The human effects of other TULPs were described, such as the TULP1 mutation and its correlation with retinitis pigmentosum type 14. Would the symptoms of a double mutation in humans be similar to that of mice? If not, does the TUB gene function similarly to other obesity-related genes, and that is why it is a good gene to study?
Is the amount of tubby that localizes to the nucleus about the same across most cell types? The review paper regarding tubby family proteins discusses how TUB tends to affect the nervous system and retina. I am wondering if the different functions that are disrupted in different cell types is cause by varying amounts of tubby protein that has localized to the nucleus.
The papers and reviews on this topic highlight TUB as a fundamental component of the metabolic system of our bodies. Yet the paper “Tubby Proteins: the Plot Thickens” stated that mice that are mutant for TUB, resulting in a phenotype identical to homozygous deletion, function under normal weight for 12 weeks. Why do you think the effects of this mutation are late-onset in these mice and not present within the developmental stage?
What is the significance of the tubby genes being linked to numerous bodily issues, beyond obesity, such as hearing loss? What do you think these numerous phenotypic results mean both for health care purposes and the specifics of mutant protein function?
In the first review listed they stated the many phenotypes caused by mutations in the "tubby family" of genes. They varied from insulin resistance to neural tube development in embryos. What is the rate and prevalence of TUB polymorphisms or mutations in the normal population and what causes these mutations to develop such drastically different phenotypes?
The underlying biochemical mechanisms stated in these articles show the significance of these genes in their association to obesity and various other phenotypic manifestations. How, though, do you believe it interacts with a change in environment? By this I mean do you think there could be a significant attempt at regulating weight in those who have a mutation in the TUB gene via exercise and diet or will these intracellular pathways solidify a perpetually obese phenotype?
In "G-protein signaling through Tubby proteins" by Santagata et al., the authors establish a model in which Tubby acts as a G-protein coupled receptor signal. Since the specific G-alpha subunit is required for Tubby to dissociate from the membrane, could mutations in that specific G-alpha subunit, PLC-beta, or the GPCR itself produce a similar phenotype? Speculatively, speaking, is there potential to treat problems with Tubby transport with drugs that target this specific GPCR?
What do you think would happen if you were to upregulate the GPCR(s) (5HT2c, I believe) that the authors think is suppressed by mutant tubby? Would this restore a non-obese phenotype to the mice, or would there be other downstream problems?
In the paper “The tubby family proteins”, the authors state “the tubby mouse shows a tripartite syndrome characterized by maturity-onset obesity, blindness and deafness”. And in the paper “Tubby proteins: the plot thickens”, the authors show progress of retinal degeneration in tubby mice. Moreover, the authors show when tubby mice gains weight, there is insulin resistance but not obvious diabetes. Since obesity can cause diabetes and diabetes can cause blindness as well, i wonder even though they couldn’t see any obvious relationship with diabetes, there might have common triggers or effects. Moreover how much environment can affect to syndrome.
Wild-type Tubby is characterized by the dual localization to the plasma membrane and nucleus of a cell. Has research implicated mutant Tubby localization preference to one of the two localizations in a pattern deviating from that expressed by the wild-type form of the protein?
The article speaks a lot about how different amounts (over expression and under expression) of the different TUB proteins can cause migratory effects. Is this due to the plasma membrane no longer being a favorable environment if there is a lot of the protein being expressed? Or are there ideas as to why the protein moves in the cell due to the level of expressions.
In the main paper it was stated that tubby translocate into nucleus due to "saturation" of specific membrane binding sites, what exactly does this mean? Is this referring to Gαq activation and the molecular activities that followed?
I'm interested to know how the loss of function in tubby affects different organisms phenotypically. How does it vary from say, mammals, to non-vertebrates, to plants? Why is it even relevant in an organism such as Arabidopsis when studying obesity?
In the Santagata et al. paper the authors state that the "COOH terminal domain binds avidly to double stranded DNA". Is anything known about what sequence tubby might bind to? Does it act as an activator or a repressor (or both) of gene transcription?
In about what fraction of cases of obesity is the Tubby gene responsible, and to what extent? How can we determine this, and what can we do to better inform the public in a way that will help maximize health benefits?