MTF1 protein lessens toxicity of mutant HTT, early study finds
Raising protein's levels may offer way of effectively treating Huntington's
Increased levels of the stress response protein MTF1 suppressed the toxic effects of the mutant huntingtin (mHTT) protein — the underlying cause of Huntington’s disease — in cellular and animal models of the neurodegenerative condition, a study showed.
Specifically, MTF1 was found to counteract mHTT-associated oxidative stress, a type of cellular damage implicated in Huntington’s and known to kill cells, and to reduce toxic mHTT clumps. It also eased motor defects in a mouse model.
These preclinical findings suggest that the delivery of MTF1 may offer a new way of treating Huntington’s, the researchers noted.
The study, “Genome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity,” was published in the journal Nature Communications.
MTF1 protein showed a capacity to resist mutant HTT-induced stress to cells
In Huntington’s, excessive repeats of three DNA building blocks — C, A, and G — in the HTT gene drive the production of an mHTT protein that can be toxic to nerve cells, resulting in the disease’s motor, cognitive, and emotional symptoms.
So far, no available Huntington’s treatments are disease modifying, able to slow or stop progression. One way of identifying targets for a potential disease-modifying therapy is to detect cellular processes that resist the impact of mHTT.
To this end, researchers in Italy conducted a genome-wide screening of mouse embryonic stem cells harboring a Huntington’s-causing HTT gene mutation. The genome comprises all the genetic information of an organism.
Mouse embryonic stem cells “bear an intact genome that is highly amenable to modification … allowing the generation of large-scale mutant libraries successfully used for genetic screenings,” the researchers wrote.
Lab-grown cells then were exposed to two chemical stressors that exacerbated the effects of mHTT, causing greater cell death. Next, the team induced mutations at random genome locations to increase the activity of neighboring genes, looking for those that protected the cells from these stressors.
Screening identified 107 genes as candidate suppressors of mHTT toxicity. Four genes with potent activity were selected for validating tests: Mtf1, Kdm2b, Kdm5b, and Fbxo34. All four candidates did not affect HTT gene activity, but they lowered HTT protein levels by 15% to 22%.
“Among all candidates, Mtf1 stood out for its capacity to confer resistance to mHTT in the presence of both stressors,” the researchers wrote.
Mtf1 encodes for MTF1, a cellular stress-sensor protein that activates certain genes in response to various stress conditions, including the accumulation of metals such as cadmium, low oxygen, and oxidative stress.
The team found that among genes affected by mHTT, 36.8% were rescued significantly with Mtf1.
Further experiments showed that the activity of 36.8% of the genes affected by mHTT was significantly rescued by Mtf1 gene overactivation. This excessive activity also lessened mHTT-associated cellular processes, including cadmium accumulation, the production of reactive oxygen species that contributes to oxidative stress, and cell death.
Notably, overactivating the Mtf1 gene in healthy cells did not significantly affect cellular growth or protect from cell stress or death, “indicating that MTF1 does not confer a generic protection,” the team wrote.
Researchers tested the impact of increasing MTF1 protein levels in a zebrafish model of Huntington’s.
Injection of mHTT in zebrafish embryos led to malformations and death, while injecting both proteins — mHTT and MTF1 — led to fewer severely malformed embryos (17% vs. 28%) and dead embryos (8.5% vs. 16.5%). This ultimately doubled the proportion of healthy zebrafish embryos (46.5% vs. 20%).
Huntington’s disease research toward a new treatment approach
A protective effect of Mtf1 also was seen in a standard mouse model of Huntington’s. To increase MTF1 levels in the mice’s brain, the researchers used a modified and harmless virus to deliver the Mtf1 gene to brain regions involved in motor function.
Treated mice showed motor performances similar to healthy mice, as well as comparable brain weight, an indirect measure of the brain shrinkage that is a common Huntington’s feature.
Brain tissue analysis revealed that increasing MFT1 levels also resulted in fewer mHTT aggregates and less oxidative stress.
Lastly, Mtf1 overactivation was found to counter mHTT by reducing oxidative stress and cell death in lab-grown human neuron precursor cells derived from a Huntington’s patient.
These findings highlight that increasing MFT1 levels “suppressed the detrimental effects caused by mHTT [in cells] and in two [animal] models” of Huntington’s disease, the researchers wrote, “indicating that delivery of Mtf1 might represent a therapeutic strategy against HD.”
Future research is needed to identify the underlying mechanisms and targets of MTF1 in Huntington’s, the scientists noted, adding that they also will be looking for small molecules that can increase Mtf1 gene activity.