Protein Implicated in Emphysema May Be Potential Therapeutic Target
Mice lacking a protein called FCHSD1 were protected from developing emphysema, a severe form of chronic obstructive pulmonary disease (COPD), according to data from a recent study.
Based on these observations, researchers say this protein could serve as a future therapeutic target for COPD.
“Our findings may also lead to a specific therapeutic strategy to ameliorate, or even halt, the progression of emphysema by inhibiting FCHSD1,” Takashi Satoh, PhD, the study’s senior author, said in a press release.
The study, “Loss of FCHSD1 leads to amelioration of chronic obstructive pulmonary disease,” was published in the journal PNAS.
Emphysema is a severe form of COPD, in which the tiny air sacs found in the lungs are damaged, leading to shortness of breath, significant lung function decline, and increased mortality. Although it appears to be triggered by environmental factors, such as cigarette smoke, little is known about how it actually starts to develop.
Understanding disease development could help researchers discover new therapies that address the condition’s root cause, rather than only managing its symptoms, as is the case with current treatments.
Past research has shown that COPD development involves numerous signaling pathways under the control of intracellular trafficking proteins. These proteins are responsible for transporting molecules from one part of the cell to the other, such as between the nucleus, where genetic information is stored, to the cell surface, where interactions between cells and other molecules take place.
After sifting through COPD-related trafficking proteins, a group of scientists from Osaka University in Japan identified a protein called FCHSD1, which appeared to become more active when exposed to chemicals that trigger emphysema in mice. Although FCHSD1 has been associated with certain diseases, it had no known function in respiratory illnesses.
To study FCHSD1’s potential role in emphysema, the investigators assessed and compared the responses of mice with and without the gene needed to make the FCHSD1 protein, after triggering the onset of emphysema by treating the animals with an enzyme called elastase.
Mice lacking the gene showed a measure of protection against emphysema, as evidenced by having fewer signs of inflammation and cell death than their peers, in whom FCHSD1 activity increased in response to elastase treatment.
To gain further insight into the mechanisms by which FCHSD1 might exert these effects, the researchers examined its interactions with other proteins.
They first observed the levels of the SIRT1 protein, which is known to reduce inflammation and to play a protective role in emphysema, declined less in the lungs of mice lacking the Fchsd1 gene, than in those of normal wild-type mice. A drop in SIRT1, the scientists suggested, could aggravate emphysema by worsening inflammation.
They also found that FCHSD1 could stop a protein called NRF2 from entering the nucleus. NRF2 is a transcription factor that normally activates antioxidant genes involved in defending cells against oxidative stress — a form of cellular damage caused by the build-up of oxidant molecules, which can also be triggered by exposure to cigarette smoke. Transcription factors are proteins that are able to control the activity of certain genes.
The researchers found that FCHSD1 attaches itself to NRF2, preventing it from entering the nucleus and activating these protective mechanisms. Conversely, when FCHSD1 is absent, NRF2’s transport into the nucleus was boosted, conferring another layer of protection against emphysema.
“Mice with a FCHSD1 deficiency showed enhanced nuclear translocation of NRF2 and a smaller reduction in SIRT1 levels, which is seen to occur as emphysema develops,” said Takahiro Kawasaki, MD, the study’s first author, “and this reduced inflammation and apoptosis of lung cells.”
“Our data provide insight into the role of FCHSD1 in stress-response sensing and as an integrator of oxidative stress,” the researchers concluded, adding that their results “may also lead to a specific therapeutic strategy to ameliorate/halt the progression of emphysema via inhibition of FCHSD1.”