€200,000 for Huntington’s disease research at the MDC
Huntington’s disease, also known as Huntington’s chorea, is an incurable hereditary disease that affects the brain. Symptoms usually begin between 35 and 45 years of age, but occasionally in childhood or in old age. Typical symptoms include motor disturbances, personality changes and dementia. It usually culminates in death within 20 years. Patients are utterly helpless at the end of their life.
To ease the horror of Huntington's disease - this is what Dr. Eduardo Silva Ramos is striving for. He found a recently unidentified protein complex that can target proteins for degradation. Together with his team colleagues, he now hopes to pave the way for a drug therapy against the insidious disease.
The disease is caused by a mutation of the Huntingtin gene. It causes the protein of the same name (HTT) to misfold in the nerve cells, resulting in gradual, unrelenting brain degeneration. It has been known for almost 30 years that the defective HTT protein plays a decisive role in Huntington’s disease. But exactly how the gene mutation is linked to the function of the protein and the disease remains unclear.
Dr Eduardo Silva Ramos, who has conducted research at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) since 2019, is following a new lead. “We were able to identify a previously unknown protein complex that can target proteins for degradation. It consists of two subunits that both interact with HTT,” reports Ramos, who works as a postdoctoral researcher in the group Proteomics and Molecular Mechanisms of Neurodegenerative Diseases led by Professor Erich E. Wanker. “The results of our experiments indicate that the protein complex plays an important role in regulating HTT protein levels.”
“It's a great feeling”
CryoEM structure of huntingtin (blue) in complex with HAP40 (magenta). Author: Harding, R.J., et al. (2021). HAP40 orchestrates huntingtin structure for differential interaction with polyglutamine expanded exon, https://doi.org/10.1101/2021.04.02.438217
Eduardo Silva Ramos has been awarded the Berman-Topper Family HD Career Development Fellowship 2021 by the Huntington’s Disease Society of America to enable him to further investigate the protein complex he discovered. The programme aims to support early career researchers for three years in a project that has the potential to provide groundbreaking new insights into the biology of Huntington’s disease. “I see this fellowship as recognition of the innovativeness of our scientific approach. It's a great feeling and it has motivated me to continue in my research career,” says the biologist. The fellowship has total allocated funding of $240,000, which equates to nearly €200,000.
Eduardo Silva Ramos and other researchers from the group led by Professor Wanker hope to find out whether and how the protein complex can be utilised for new treatment methods. The team will start by investigating the mechanisms of interaction between the protein complex and HTT. The researchers will place a particular focus on ubiquitination. “Ubiquitin is a protein that can be attached to other proteins to target them for degradation, such as misfolded proteins in neurons,” explains Eduardo Silva Ramos. “The subunits of our protein complex can attach ubiquitin chains. This may reduce the amount of disease-causing HTT in the neurons.” In parallel, the researchers intend to carry out drug screening in the hope of being able to identify molecules that stabilise the interaction between the defective HTT and the protein complex. “If we succeed, this may pave the way towards treating this insidious disease with medication,” says Eduardo Silva Ramos.
Text: Wiebke Peters
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