High TSPO protein levels found protective in fruit fly model of FA
Preclinical findings suggest protein may be therapeutic target for disease
Increasing the levels of a protein known as TSPO in glial cells — which provide nutrients to nerve cells and help with their communication — extended survival and improved mobility in a fruit fly model of Friedreich’s ataxia (FA).
These preclinical findings suggest that “TSPO might be a relevant therapeutic target for this disease,” the researchers wrote.
The study, “Glial overexpression of Tspo extends lifespan and protects against frataxin deficiency in Drosophila,” was published in the journal Biochimie.
While these results are promising, the researchers noted that their work is in its very early stages.
“Overall, TSPO function still remains elusive … and multiple potential mechanisms remain to be explored in order to understand the protective effects observed here,” the team wrote.
TSPO protein found to extend survival, improve mobility in fruit flies
FA is caused by mutations in the FXN gene, which carries the instructions to make frataxin. This protein is important for the function of mitochondria, the cellular energy production centers.
The most common mutations in FA consist of an excessive number of a trio of nucleotides, or DNA building blocks. Specifically, these are one guanine (G) and two adenines (A). Having more GAA repeats correlates with greater frataxin deficiency, an earlier onset of disease, more severe symptoms, and faster disease progression.
In healthy people, the nucleotide trio is repeated from five to 33 times; people with FA have significantly more, ranging from 66 to more than 1,000.
TSPO is a mitochondrial protein whose levels are abnormally high in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. The protein is a marker of inflammation in the brain and spinal cord, and has been proposed as a potential therapeutic target for neurological conditions. A recent study suggested higher levels of TSPO in areas of neurodegeneration in the brain of FA patients.
The researchers, from France, found an increase in the expression, or activity, of the Tspo gene, which codes for the protein of the same name, in a fruit fly model of FA. To understand the impact of high levels of TSPO in FA, they now developed a different fruit fly model with fewer GAA repeats as a way of studying milder disease severity.
The new model recapitulated the hallmarks of FA, including a shorter lifespan, locomotion or mobility problems, and high susceptibility to oxidative stress, a type of cellular damage. Oxidative stress arises as a result of an imbalance between toxic reactive oxygen species and the antioxidant molecules needed to counteract them. This type of damage is closely linked to mitochondrial dysfunction.
In agreement with the team’s previous observations, Tspo gene activity was significantly increased in the heads of the newly generated fruit fly model. Compared with control flies of the same age, Tspo gene activity in the head increased by 76% in one day, and by 40% after seven days. Conversely, TSPO levels were low in the intestine. “Thus, a strong frataxin deficiency did not induce Tspo overexpression in this organ,” the scientists wrote.
This study highlights protective effects of glial TSPO in [fruit flies] both in a neurodegenerative and a healthy context.
The researchers then engineered the fruit flies to have TSPO levels that were even higher than normal levels. An increase from early development led to a 43% extension in average survival but did not affect frataxin levels.
“Considering the well-described increase of Tspo expression in glial cells under various neuropathological conditions in mammals … we asked if glial-specific overexpression of Tspo could be responsible or participate in this protective effect,” the team wrote.
The results showed that boosting the protein’s levels from early development or only in adulthood led to a significant increase in the flies’ lifespan. Better locomotion also was noted.
Finally, in healthy adult flies, high levels of TSPO in glial cells also prolonged survival, while the opposite was seen when this overexpression was in neurons (nerve cells).
Overall, “this study highlights protective effects of glial TSPO in [fruit flies] both in a neurodegenerative and a healthy context,” the researchers wrote. Still, the mechanisms underlying these effects “remain to be elucidated.”
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