Year of selection 2016
Institution Leibniz-Institut für Molekulare Pharmakologie (FMP)
Huntington’s disease (HD) is a hereditary neurodegenerative disorder that causes the progressive loss of cognitive and motor functions and ultimately leads to death. Today, there are no preventive treatments nor cures for this devastating, age-related disease that affects an average of 5 to 10 people per 100,000, albeit with a highly variable worldwide prevalence. Although the mutated gene responsible for the disease is known, the exact mechanisms leading to the premature death of neurons in patients with HD are not yet fully understood. Dr. Katrin Jünemann aims to elucidate them. Her focus is on finding a way to avoid the accumulation of toxic proteins in the brain, a hallmark of HD and of other neurodegenerative diseases (ND) in general.
Indeed, one of the neurological consequences of Huntington’s disease is the accumulation of the mutant protein called huntingtin (mHtt) in brain cells. This toxic build-up ultimately results in the death of brain cells, which in turn causes devastating symptoms such as psychiatric and behavioural problems, difficulties with feeding and communication, and abnormal movements. In healthy individuals, the huntingtin protein, like all other proteins, is synthesized and then degraded, which allows for the constant renewal and regulation of cells. However, with mHtt proteins, the degradation mechanisms appear to be inefficient—a phenomenon that is made even worse by aging. “Every cell has a trash bin. The older you get, the harder the cells can deal with emptying those thrash bins,” explains Dr. Katrin Jünemann. Her objective is to elucidate why the degradation process is jeopardized, in order to develop a therapeutic strategy to delay or even prevent the onset of HD through artificially improving degradation of mHtt.
Investigating the degradation mechanisms of mutant huntingtin proteins
One of the ways in which a protein is degraded is through a process that labels them for destruction, the equivalent of the ‘kiss of death’ for a protein. This clearance system involves two successive steps: tagging of the protein to be eliminated by the attachment of molecules called ubiquitin, and subsequent degradation of the tagged protein. According to Dr. Katrin Jünemann’s previous work, this mechanism is at the heart of Huntington’s disease. “My past research clearly showed that mHtt ubiquitination and clearance appears to be inefficient, leading to accumulation of the toxic mHtt ,” she explains. Building on this knowledge, Dr. Jünemann intends to thoroughly study the precise molecular mechanisms of mHtt ubiquitin tagging and degradation in an age-dependent manner. Her methodology will include working with a worm called C. elegans. These model organisms exhibit the same symptoms as humans when given the mutated gene. They are particularly valuable to studies on neurodegenerative diseases because of their short lifespan.
“Never before has the population of the world been so old,” stresses Dr. Jünemann. “Neurodegenerative diseases represent an increasingly pressing issue, not only regarding health, but also society, economy and politics. However, compared to other research fields, such as cancer or heart disease, funds dedicated to ND are insufficient in regard to the number of cases and the societal cost.” With her research, Dr. Katrin Jünemann aims to contribute to a better understanding of Huntington’s disease and, by extension, of other comparable neurodegenerative diseases. The ultimate goal is to develop a treatment capable of delaying, if not preventing, the onset of symptoms in patients diagnosed with the mutated gene.