Researchers at the VIB-KU Leuven Center in Belgium have identified proteins involved in the development and progression of FTD and amyotrophic lateral sclerosis (ALS).  

The researchers hoped to understand the underlying mechanisms of the c9orf72 gene mutation and how it can cause FTD and ALS. In two separate studies, they found three key proteins that could be useful as therapeutic targets for clinical treatments.  

Mutation of c9orf72 typically involves a continual repetition of a DNA sequence, which can cause FTD in ways that still are uncertain.  

The first study, published in Alzheimer’s and Dementia, sought to investigate the ways that this DNA replication can create toxic dipeptide repeat proteins (DPRs) believed to play a role in FTD and ALS progression. The research team, led by Wenting Guo, PhD, discovered that suppressing the NEK6 protein reversed the damage caused by DNA replication, and could counteract the effects of DPRs. When the brain is injured, NEK6 is one of the signals that trigger inflammation; suppressing it can block or reduce neuroinflammation that is common in FTD. 

“Our study offers a complete preclinical roadmap to discover and validate new therapeutic targets for C9-related ALS and FTD,” Dr. Guo said. “We also provide a solid foundation for further drug development and hopefully will pave the way to clinical applications.” 

The second study, published in Acta Neurologica, focused on investigating the toxicity of RNA produced by the C9 mutation.  

Using zebrafish models, researcher Elke Braems and her team found that elevated levels of the HNRNPK protein (which controls how RNA is edited) can reverse the damage caused to neurons by toxic RNA. Likewise, the team found that the RRM2 protein (which promotes the creation of the chemical building blocks needed to make or repair DNA), which is impaired by C9 mutations, can respond to DNA damage, and could be a promising target for future treatments.  

“During my master thesis, we used this zebrafish model as a screening tool and revealed HNRNPK as a modifier of RNA toxicity. This was the foundation for my current PhD project in which we successfully unraveled the exact mechanism of the HNRNPK protein in C9-related ALS,” said Braems.  

FTD research is ongoing, with the aim of improving diagnosis and treatment. To learn more about current studies and how to participate, sign up for the FTD Disorders Registry. People with an FTD diagnosis and care partners can register to contribute their experiences to aid in research or to take part in clinical studies.