Molecular link found between aging and a major genetic cause of 2 neurodegenerative disorders.
Although age has been determined to be a primary risk factor for almost all neurodegenerative disorders, little has been known about this connection. However, recent findings published in Cell may lead to new treatment targets for diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
In the study, researchers found a molecular link between aging and a major genetic cause of both ALS and FTD. The researchers modeled the reduced levels of the TBK1 protein found in patients with ALS and FTD by creating mice that had only 1 functional copy of the gene that produces TBK1.
In some cases, patients with both ALS and FTD carry genetic mutations that cause the partial dysfunction of TBK1, according to the researchers.
Mice who carried the gene were healthy and similar in appearance to normal mice, but those without the gene died before birth. The researchers found that blocking the activity of RIPK1, another protein known to play a role in programmed cell death, neuroinflammation, and neurodegenerative disease, allowed the mice to survive and become healthy adults. Furthermore, they determined that TBK1 normally functions to inhibit the activity of RIPK1 during embryonic development.
The researchers examined another protein, called TAK1, which is also known to inhibit RIPK1 function. They observed TAK1 expression in human brains, finding a significant decline with age. TAK1 expression was further reduced in the brains of patients with ALS compared with the brains of similarly aged healthy individuals.
Next, the researchers modeled the interaction between partial loss of TBK1 and TAK1 with aging in mice that expressed half the usual amount of the proteins. Mice with reductions in both TBK1 and TAK1 displayed traits associated with ALS and FTD. Similarly, the mice had a reduction in the number of neurons in the brain and increased motor neuron dysfunction and cell death. However, inhibiting RIPK1 activity independently of TBK1 and TAK1 appeared to reverse the symptoms, according to the researchers.
They noted that TAK1 and TBK1 appeared to work together to suppress RIPK1 activity, possibly explaining why individuals with TBK1 mutations do not develop neurodegenerative disorders until they age, after their TAK1 levels decline.
While clinical trials are underway to test the safety and efficacy of drugs that inhibit RIPK1 activity, there are currently no effective therapies developed yet for neurodegenerative disorders.
“I think the next couple of years will reveal whether RIPK1 inhibitors can help ALS and FTD patients,” study author Junying Yuan, PhD, Harvard Medical School Elizabeth D. Hay professor of cell biology, said in a press release. “I think our study makes us more confident those efforts might work.”
Xu D, Jin T, Zhu H, et al. TBK1 suppresses RIPK1-driven apoptosis and inflammation during development and in aging. Cell. 2018. Doi: https://doi.org/10.1016/j.cell.2018.07.041
Aging Connection [news release]. Harvard Medical School’s website. https://hms.harvard.edu/news/aging-connection. Accessed August 23, 2018.