Molecular Link Between Aging and Rare Neurodegenerative Diseases Identified

Investigators from Harvard Medical School have begun defining the elusive relationship between aging and neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), both of which share genetic risk factors.

The team found that aging facilitates RIPK1 activation by reducing TAK1 expression, thus indicating that aging encourages predisposed genetic risk factors for ALS and FTD. With the identified molecular link, investigators have also provided new targets for future neurodegenerative therapies.

“My lab has been studying the role of RIPK1 in mediating neuroinflammation and neurodegeneration for more than 20 years,” study investigator Junying Yuan, PhD, Harvard Medical School, told Rare Disease Report^®. “The question, how aging promotes the activation of RIPK1 to mediate neurodegeneration, has also been on my mind for 20 years. I am so glad that we now have got this first insight into this question.”

Since partial loss of function of TBK1 is a major genetic cause for ALS and FTD comorbidity, Dr. Yuan and her Harvard team sought to investigate how TBK1’s loss of function contributes to age-dependent neurodegeneration. In previous studies, Dr. Yuan and her colleagues demonstrated TBK1’s involvement in a form of programmed cell death and in neuroinflammation in neurodegenerative diseases.

By creating and using mice models that contained only 1 functional copy of the gene that produces TBK1, Dr. Yuang and her team found that by blocking the activity of RIPK1, mice without TBK1 were able to survive birth and grow into healthy adults. The team also uncovered that during embryonic development, TBK1 normally inhibits the activity of RIPK1.

Due to their findings, the team decided to research another protein, TAK1, since it is known to inhibit RIPK1 function. Upon analysis of TAK1 expression in human brains, the team found that, with age, TAK1 expression diminishes significantly. TAK1 expression was observed to further diminish in the brains of ALS patients compared with those without the condition who were similar in age.

Dr. Yuan and her team also evaluated the interaction between partial loss of TBK1 and TAK1 and aging by modifying mice to express half the usual amount of TBK1 and half the usual amount of TAK1 in their microglia. Upon further analysis, motor deficits, hind limb weakness, anxiety-like behavior in new environments, and changes in brain chemistry were observed in the mice—all traits associated with ALS and FTD. The mice were also observed to have increased motor neuron dysfunction, cell death, and a reduction in the number of neurons in the brain.

However, when RIPK1 activity was inhibited independently of TBK1 and TAK1, a reversal in symptoms was observed.

The investigators concluded that suppression of the activity of RIPK1 may likely be due to a joint effort between TAK1 and TBK1; it appears that if either TAK1 or TBK1 “fail” to inhibit RIPK1 activity, they are able to compensate for each other. However, if both begin to fail, RIPK1 activity increases, which can result in cell death and neuroinflammation.

Dr. Yuan postulated that this may be why individuals with TBK1 mutations do not develop ALS and FTD until they become older, when TAK1 levels decline with age, in a recent statement.

“Aging is the biggest risk factor for neurodegenerative diseases,” she added. “However, the mechanism by which aging acts to promote neurodegeneration is unclear. This paper provides the first insight into the molecular mechanism by which aging of human brains interacts with genetic risk factors to promote the onset of neurodegeneration.”

Several clinical trials evaluating the safety and efficacy of drugs that block RIPK1 activity in neurodegenerative and chronic inflammatory diseases are in the works thanks to her team’s newfound data, Dr. Yuan added.

“We are going to test our findings, i.e. down-regulation of TAK1, in a variety of animal models of neurodegeneration,” Dr. Yuan said. “Our finding supports the development of RIPK1 inhibitors in a variety of human neurodegenerative diseases. Denali Therapeutics, which licensed our RIPK1 inhibitors, have advanced a RIPK1 inhibitor into a phase 1 human clinical study for [the development of a] new drug for the treatment of Alzheimer’s disease and ALS.”